cpanadaian jtourhnal ofolog y - canadian journal of...

Lymphomas of the Breast

Kulcsar Lecture

Canadian Journal of

Pathology

Publications Agreement Number 40025049 • ISSN 1918-915X • Vol. 1, Issue 4 • Winter 2009

www.cap-acp.org

Official Publication of the Canadian Association of Pathologists

VOLUME 1, ISSUE 4 2009

About the Cover

5 Editorial/ÉditorialJ. Godfrey Heathcote, MA, MBBChir, PhD, FRCPC

EDITOR-IN-CHIEFJ. Godfrey Heathcote

EDITORIAL BOARD

Manon Auger, MD, FRCPC, Cytopathology; Calvino Cheng, BSc, MD, FRCPC, Pathology Informatics

and Quality Management; Eleftherios Diamandis, BSc, MD, PhD, FRCPC, Medical Biochemistry;

David K. Driman, MB ChB, FRCPC, Anatomical Pathology; Todd F. Hatchette, BSc, MD, FRCPC, Medical Microbiology;

Michael J. Shkrum, MD, FRCPC, Forensic Pathology; Louis D. Wadsworth, MB ChB, FRCPath, FRCPC, Hematopathology

C AP A SSOCIATION MANAGER Danièle Saintonge

MANAGING EDITORSusan Harrison

COPY EDITORSScott Bryant, Susan Harrison

ART DIRECTORAndrea Brierley, [email protected]

TR ANSL ATOR SMarie Dumont, Julie Paradis

SALE S AND CIRCUL ATION COORDINATORBrenda Robinson, [email protected]

ACCOUNTINGSusan McClung

GROUP PUBLISHERJohn D. Birkby, [email protected]

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––Canadian Journal of Pathology is published four times annually by

Andrew John Publishing Inc., with offices at 115 King Street West, Dundas, On, Canada L9H 1V1.

We welcome editorial submissions but cannot assume responsibility or commitment for unsolicited material. Any editorial material, including photographs that are accepted from an unsolicited

contributor, will become the property of Andrew John Publishing Inc.

FEEDBACKWe welcome your views and comments. Please send them to

Andrew John Publishing Inc., 115 King Street West, Dundas, On, Canada L9H 1V1.

Copyright 2009 by Andrew John Publishing Inc. All rights reserved.Reprinting in part or in whole is forbidden without express

written consent from the publisher.

INDIVIDUAL COPIE SIndividual copies may be purchased for a price of $19.95 Canadian. Bulkorders may be purchased at a discounted price with a minimum order of

25 copies. Please contact Ms. Brenda Robinson at (905) 628-4309 [email protected] for

more information and specific pricing.

Publications Agreement Number 40025049 • ISSN 1918-915XReturn undeliverable Canadian Addresses to:

115 King Street West, Suite 220, Dundas Ontario L9H 1V1

Canadian Journal of Pathology • Volume 1, Issue 4, 2009 Contents

CAP-ACP News

Original Articles

For Instructions to Authors, please visitwww.andrewjohnpublishing.com/CJP/instructionstoauthors.html

7 Message from the PresidentLaurette Geldenhuys, MBBCH, FFPATH, MMED, FRCPC, FIAC, MAEd

Obituaries Dr. George Anderson and Dr. Michael McNeely

Opinion

10 The Pathologist as an Expert WitnessHarry E. Emson, MA, MD, FRCPC

Lymphomas of the Breast: A Clinicopathological Study Over 12 YearsMonalisa Sur, MBBS, FCPath (SA), FRCPath (UK), FRCPC, Prashant K. Dhamanaskar, MBBS, MD, FRCPC, Noori Akhtar-Danesh, MSc, PhD (Newcastle), Leela Elavathil, MD, FRCPC

Tissue Engineering the Nucleus Pulposus: Is It Feasible?Emma V. Dare, PhD, Rita A. Kandel, MD

Surgical Pathology Quality Assurance/Quality Improvementin a Community Hospital: A Year in ReviewStanley Todd, MD, Mukund Tinguria, MD, P. Wentworth, MD, A. Croal, MD, Katherine Chorneyko, MD

Kulcsar Leture 2009: Highlights from the National Cancer InstituteThyroid Fine Needle Aspiration State of the Science ConferenceManon Auger, MD, FRCP(C)

This image shows characteristicnuclear features of papillary thyroid carcinoma with the ovalnuclei, fine chromatin, nuclear grooves, micronucleoli, and intranuclear inclusions.

8

12

21

27

32

FSC Logo/Info Here

(Recycled Paper Content information inserted by Printer)

Canadian Journal of P athology 5Winter 2009

Among the reminiscences of past

presidents of the Canadian Association

of Pathologists (CAP–ACP) published in the

first issue of this journal, two in particular

struck a chord with me.

In his piece, Dr. Diponkar Banerjee noted

that, when he became president, “the CAP

was struggling with some of the unilateral

decisions made by the Royal College

of Physicians of Canada regarding the

restructuring of laboratory medicine training

programs.” The furor over the status of

neuropathology and general pathology

programs has abated, but it is far

from certain that they will remain primary disciplines in the

long term. What was disconcerting about the Royal College

approach to these programs was the fact that pathologists

and laboratory physicians appeared to have little say in the

matter. Scant attention was paid to the societal need for

general pathologists in many parts of this country or the

fact that many of the international leaders of neuropathol-

ogy trained in Canadian neuropathology programs. It seems

likely that the future of these two programs will be revisited,

perhaps repeatedly or until the Royal College succeeds in

eliminating them. This past August there was an

announcement that the Committee of Specialties of the

Royal College had endorsed a proposal that medical

biochemistry cease to be a primary discipline and become a

subspecialty of internal medicine or pediatrics. The Office

of Education was to conduct a consultation with

stakeholders, but, as I write this in late October, it is far from

clear that this will include the wider community of

pathologists and laboratory physicians. In future issues of

the journal, I hope to explore further the arguments about

residency training in the laboratory disciplines.

While the Royal College concentrates on the implementation

of educational principles, many pathologists feel that it has

neglected its role in fostering the development of its

professional disciplines. Given the number of training

programs it accredits, this is perhaps

inevitable. Nevertheless, it clearly puts

Canadian pathologists and laboratory

physicians at a disadvantage compared with

our colleagues in the United Kingdom and

Australasia. Some of the recent problems that

have focused public attention on pathology

would have been dealt with more effectively

by the Royal College of Pathologists (U.K.),

which has long had an established process for

dealing fairly and expeditiously with

pathologists whose performance has been

judged to be substandard.

Dr. Paul Manley, in his reminiscence, speaks

of the need for “one national pathology association to make

a meaningful and thoughtful contribution to continuing

education of laboratory professionals, and to residency

teaching and preparation for … professional careers.” The

CAP-ACP has an important role in this, but we cannot

ignore the successful professional societies that the bio-

chemists and microbiologists have established. Perhaps the

time is ripe for the creation of a national umbrella

organization, along the lines of an independent (Royal)

College, that will protect the interests of all laboratory

disciplines and bring us closer together, rather than pushing

us farther apart. Although there have been examples of first-

class diagnostic laboratories run by clinicians, with the

administrative and scientific complexity of modern

laboratory practice I have concerns that any reversion to this

arrangement would not be in the best interests of the

patients we serve or those we teach.

Whether you agree or disagree with my personal

opinion, I invite you to share your thoughts with your

colleagues in the correspondence pages of the

journal. This subject, above all, is worthy of debate.

J. Godfrey Heathcote

Editor-in-Chief

Editorial

Winter 20096 Canadian Journal of P athology

Deux des articles d’anciens présidents de CAP-ACP relatant

leurs souvenirs, parus dans le premier numéro de la revue,

ont particulièrement capté mon attention.

D’abord, celui du Dr Diponkar Banerjee qui souligne que,

lorsqu’il est devenu président de l’Association, « CAP-ACP

était en désaccord au sujet de décisions unilatérales du

Collège royal des médecins et chirurgiens du Canada à

propos de la restructuration des programmes de formation

en médecine de laboratoire. » Le tollé soulevé par la question

des programmes de neuropathologie et de pathologie

générale s’est apaisé, mais c’est loin d’être certain que ces

deux disciplines conserveront leur position à long terme. Ce

qui nous a déconcertés dans l’attitude du Collège royal est

le fait que les pathologistes et les médecins de laboratoire

n’ont pas eu voix au chapitre manifestement. Le Collège n’a

pas accordé beaucoup d’importance aux besoins sociétaux

en pathologistes généraux dans nombre de régions du pays

ni au fait que de nombreux neuropathologistes chefs de file

dans leur domaine sur la scène internationale ont été formés

au Canada dans les programmes en vigueur. Selon toute

probabilité, l’avenir de ces deux programmes sera débattu

encore et encore ou jusqu’à ce que le Collège royal parvienne

à les éliminer. Le Comité des spécialités du Collège royal a

entériné en août dernier la proposition voulant que la

biochimie médicale ne soit plus une discipline primaire,

mais une surspécialité de la médecine interne ou de la

pédiatrie. Le Bureau de l’éducation doit consulter des

intervenants sur ce sujet, mais, au moment où j’écris ces

lignes, soit la fin d’octobre, on ne sait toujours pas si la

grande communauté des pathologistes et des médecins de

laboratoire sera du nombre de ces intervenants. Dans de

prochains numéros de la revue, j’espère pouvoir aborder en

profondeur l’argumentation sur la formation en résidence

dans les disciplines de laboratoire.

Cependant que le Collège royal se concentre sur la mise en

œuvre de principes éducatifs, les pathologistes sont

nombreux à estimer qu’il néglige son rôle de promotion du

perfectionnement de ses disciplines professionnelles. Étant

donné le nombre de programmes de formation qu’il agrée,

cela est sans doute inévitable. Néanmoins, cette situation est

nettement désavantageuse pour les pathologistes et les

médecins de laboratoire canadiens par rapport aux collègues

du Royaume-Uni et de l’Australasie. Il appert que le Collège

royal des pathologistes du Royaume-Uni, qui a établi voilà

longtemps déjà un processus juste et expéditif de

rectification du rendement non conforme aux normes,

aurait su régler efficacement et promptement certains des

problèmes en pathologie qui ont suscité l’inquiétude du

public récemment.

En se remémorant son passage à la présidence, le Dr Paul

Manley aborde la nécessité « qu’une association canadienne

de pathologie contribue véritablement à la formation

continue des professionnels de laboratoire, ainsi qu’à

l’enseignement durant la résidence et à la préparation en

vue… de la carrière. » CAP-ACP a un rôle important à jouer

sur ce plan, mais nous ne pouvons ignorer les sociétés

professionnelles très actives qu’ont formées les biochimistes

et les microbiologistes. Peut-être le moment est-il propice à

la création d’une organisation de coordination

pancanadienne, à l’image d’un collège (royal) indépendant,

qui défendrait les intérêts de toutes les disciplines de

laboratoire et nous rapprocherait, plutôt que nous éloigner,

les uns des autres. Il y a eu bien sûr des laboratoires

exemplaires à vocation diagnostique dirigés par des

cliniciens, mais je suis convaincu qu’un retour en arrière de

la sorte ne serait pas bénéfique pour nos patients ni pour

nos étudiants au vu de la complexité administrative et

scientifique de la pratique de laboratoire moderne.

Que vous soyez d’accord avec moi sur ce sujet ou pas,

n’hésitez pas à me faire part, ainsi qu’à vos collègues, de vos

observations dans le courrier des lecteurs. S’il est un sujet

dont il faut débattre, c’est bien celui-là.

J. Godfrey Heathcote

Rédacteur en chef

Éditorial


CAP-ACP NEWS

Dear CAP-ACP Members,

Iam delighted to be able to update you ona number of projects that the CAP-ACP

Executive has been working on since our

successful 60th Annual Meeting in Halifax in

July. The many seeds that our previous

president, Jagdish Butany, sowed have

germinated, and the young seedlings are

starting to flourish.

As you may have noticed, we are using the

acronym CAP-ACP rather than CAP to refer

to our organization. This not only avoids

confusion with the College of American

Pathologists (CAP) but, more importantly, symbolizes the

national nature of our organization, inclusive of our

colleagues in Quebec and New Brunswick.

Speaking of the CAP, we continue our collaboration with

them on the development of synoptic reporting for cancer

specimens and are close to finalizing a memorandum of

understanding regarding the use of CAP checklists and

Canadian representation on the CAP cancer checklist

committees. The CAP-ACP is very grateful to the Canadian

Partnership Against Cancer (CPAC), which is playing a

major role in facilitating this collaboration, with the help of

John Srigley and Andrea Maclean.

CPAC is also supporting our continuing professional

development with a generous grant and is facilitating

participation by patient interest groups in the CAP-ACP

Council. The CAP-ACP has now finalized an agreement

with objective pathology to assist with the development of

online continuing professional development, under the

leadership of Joan Sweet.

The CAP-ACP is working with Accreditation Canada and

the Canadian Standards Association to evaluate and develop

an action plan to improve and streamline laboratory

accreditation in Canada with the input of existing provincial

accreditation bodies. We are also participating in the Royal

College Task Force on Laboratory Medicine and hope to

increase communication with provincial

pathology associations on matters of common

interest. A number of subcommittees are

working, including a Task Force on the

Development of Guidelines for Investigation

of Irregularities in Laboratory Medicine,

chaired by Diponkar Banerjee, a Mission

Statement Committee, chaired by Chris Nau-

gler, and a committee developing guidelines

for KRAS testing, chaired by Alan Spatz.

The document “Best Practice Recommendations

for Standardization of Immunohistochemistry

Tests,” developed under the leadership of

Emina Torlakovic, has been accepted for

publication in the American Journal of Clinical Pathology,

and the document “Guidelines for Measurement of

Pathologist Workload” is being prepared for publication by

Raymond Maung.

The Annual Meetings Committee, with annual meetings

chair Avrum Gotlieb, local organizing chair Dragana

Pilavdzic, continuing professional development chair Joan

Sweet, and a number of section chairs and other members,

is putting together an excellent program for the upcoming

Annual Meeting in Montreal. There will be an emphasis on

quality issues, and the meeting will feature the debut of new

special interest groups in areas such as international health

and informatics.

At the CAP-ACP Secretariat, all the above activity is calmly

kept on track by our administrator, Daniele Saintonge. We

welcome input from the membership on any matter of in-

terest to the community of pathologists and encourage your

active involvement.

Best wishes for a blessed Hanukkah, Christmas, and New

Year.

Laurette Geldenhuys

President

Message from the President


CAP-ACP NEWS

Dr. George Anderson (1928–2009)Dr. George Anderson was born in 1928 in Edinburgh, Scotland, and received his medical degree from Guy’sHospital in London. He immigrated to Canada in 1956, and after a year’s internship at the Royal VictoriaHospital in Montreal, took his pathology training at the Ottawa Civic Hospital and was certified by theRoyal College of Physicians and Surgeons of Canada in 1961. He was staff pathologist at the Ottawa CivicHospital from 1961 to 1968 and served as medical director of the Red Cross Blood Transfusion Service forEastern Ontario from 1961 to 1965. From 1968 to 1974, Dr. Anderson was associate director of the Department of Pathology at the Royal Jubilee Hospital in Victoria, and from 1974 to 1979, was director of the Cytology Service at the Victoria General Hospital in Halifax. In 1979, Dr. Anderson movedto Vancouver to become director of laboratories at the Cancer Control Agency of British Columbia, andfrom 1985 to 1993 was the director of the Division of Cytology at the BC Cancer Agency. As member of theCanadian Society of Cytology since 1961, Dr. Anderson served as secretary-treasurer and president in theearly days and as secretary on a second occasion from 1979 to 1982, and was president for the second timefrom 1990 to 1991. Dr. Anderson retired in Victoria in 1997, and he died in 2009 at the age of 81.

Dr. Michael McNeely (1944–2009)Dr. Michael McNeely was born in Toronto in 1944 and received his early schooling in Victoria, British Columbia. He obtained his medical degree from the University of Manitoba in 1969, and then trained inlaboratory medicine at Hartford, Connecticut, with Dr. William Sunderman until 1973. He received a fellowship in medical biochemistry in 1974. For a short while, he worked at Mount Sinai Hospital in Toronto,but in 1976, returned to Victoria where he was laboratory director and president of the Medical Laboratories until 2005. After his retirement from the laboratory, he worked as a consultant to theBC government for the Electronic Health Services Project. He was a pioneer in the field of medical informatics and made some of his most important contributions here. Dr. McNeely was nominated as anhonorary member of the CAP-ACP in 2004 and received the Distinguished Service Award. Dr. McNeelypassed away in the fall of 2009.

Obituaries


Executive Committee

PresidentDr. Laurette Geldenhuys

Vice-PresidentDr. Iakovina Alexopoulou

Past-PresidentDr. Jagdish Butany

Secretary-TreasurerDr. Brian Cummings

Annual Meeting ChairDr. Avrum Gotlieb

Members-at-LargeDr. Emina TorlakovicDr. Raymond Maung

Continuing Professional DevelopmentDr. Joan Sweet

Resource Development ChairDr. Christopher Naugler

Web Editor Dr. Tadaaki Hiruki

Association ManagerMrs. Danièle Saintonge

CAP-ACP NEWS

Dr. Jared Schwartz (right), president of the College of AmericanPathologists (CAP), presents the Presidents Certificate and Silvermedal, honouring Dr. Jagdish Butany (past president of the CanadianAssociation of Pathologists), October 9, 2009, in Washington, DC, atthe CAP House of Delegates Annual Dinner.

Dr. Butany Honoured by CAP


Harry E. Emson, MA, MD, FRCPC

In the past, pathologists in most parts of Canada couldmake a choice as to their involvement with the legal system, and its degree. Pathologists could choose whetheror not to do medicolegal autopsies either in a coroner’s ormedical examiner’s system. However, in the more remoteand less populated regions, involvement with the legal system was not always possible to decline and circumstancescould arise anywhere in which pathologists, from no desireor choice of their own, found themselves involved with casesthat proceeded to court hearings and in which they weresummoned to give evidence. For all of us, it is necessary toconsider this eventuality in advance and to define our beliefsand attitudes in the event of becoming involved in the legalsystem.The legal system in Canada, in those of its aspects withwhich a pathologist may become involved, is almost entirelybased on the adversarial principle. Lawyers are trained inthis way from their first day in law school. It permeates andimbues their lives, and many of them find it difficult or impossible to think in any other way. This principle believesthat a legal case is best solved by reducing it to a single simplequestion and deciding the answer by a court hearing beforea judge, often sitting with a jury, and conducted as a gladiatorial contest in which the parties to the controversyare represented by lawyers – “advocates” acting as “counsel.”The questions are put to witnesses in various ways, and theanswer to each individual question is sought in opposingterms – yes or no, right or wrong, black or white. On thesum of these answers, the judge or jury decides the answerto the question posed: for example, did A kill B under thecircumstances defined by the law as murder?Pathologists do not think in this way, nor do any physicians.They seek a much vaguer and ill-defined concept of the totaltruth of a situation, which in many cases remains fuzzyaround its edges, despite all attempts at clarity and precision.They find the adversarial method alien, frequently frustrating, unproductive, and often unpleasant. However,when summoned to court, we are on the law’s grounds and,to a degree, are subject to its rules. Commitment to the adversarial system is implicit from the first formal contact,the subpoena to a witness, that identifies the witness as being

summoned because he or she is thought able to give evidence for one side of the case or the other; it explicitlyconscripts the pathologist onto one side, one team, usuallythat for the prosecution.It is very easy to find fault with the adversarial system, andto pick holes in it, until one tries to find a better alternative;and in any event, this option is not in practice open to us. Itdoes break down very obviously in some of its applications,and to some extent, the law has accepted this and sought alternatives, notably in family law, with which the pathologist is rarely concerned. In the courtroom, the adversarial system entitles counsel to the most minute inquiry into the credentials, training, experience, and beliefsof the witness, which is legitimate; although questions basedon false implications of the type, “When did you stop beating your wife?” may also be raised. The desire of the law for a single simple answer and thebelief of the pathologist in complex and interacting multiplecauses may be a source of frustration. I remember from myearly years in Saskatchewan a case in which a young womandied. She had been beaten more spectacularly than seriously,was drunk, and was exposed to a cold winter night. I statedthat these factors all contributed to her death and that Icould not quantify the contribution of each. I got into deeptrouble in the witness box for sticking to this opinion ratherthan isolating a single cause of death. I think it was fortunatethat in those days I was a stubborn young man – some saidpig-headed – and the case did encapsulate for me at an earlyage some of the problems I was going to face if I chose tocontinue in medicolegal work.It may be difficult for the pathologist not to become a partisan, for instance, in the death of a child following sexualassault. The pathologist is never in possession of all the factsof a case; he or she has performed a minute and exact analysis of a small section of the evidence, which may beconclusive in such matters as a cause of death but totallylacking in other circumstances surrounding the death. If thefacts are clear, their interpretation may be the subject of different opinions. For instance, regarding orbitalhematomas in death from a gunshot wound of the head, arethese the result of antecedent external assault or of increased

The Pathologist as an Expert Witness

Harry E. Emson, MA, MD, FRCPC, is emeritus professor of pathology at the University of Saskatchewan and holds a diplomain medical law and ethics. He is based in Saskatoon, Saskatchewan.

OPINION


intracranial pressure? Or how did an overdose of a toxic substance come to be taken? – a question better addressedwithin the expertise of a toxicologist. Whenever pathologistsstep outside their very narrow bounds of certainty, theyshould bear in mind, irrespective of their personal religiousbelief, the words of Oliver Cromwell: “I beseech thee, in thebowels of Christ, think it possible that ye may be mistaken.”There is one type of counsel, much more dangerous thanthe old exponents of bluff and bluster, who will profess incompetence in the subtleties of medical evidence, flatterthe witness into an inflated belief of his or her own omniscience, and, having lured the pathologist onto the tipof a bough of speculation, briskly saw it off at its proximalend. One phrase that the pathologist should never be afraidof using is, “I do not know.”There is another, antithetical belief in the role of the expertwitness to which the law pays some attention. This is to regard the expert witness as an independent person bringingeducation, training, and experience to the court as a wholerather than to one side of the case or the other, in the hopethat this may assist the court to come to a just conclusion.Although this is sometimes more of a token genuflectionthan a true commitment, the Goudge Inquiry in Ontariodid emphasize its importance. The expert is neither a parti-san nor an advocate, hired by one side or the other; thoughunder the adversarial system, counsel for either side will en-deavour to extract from the expert’s evidence those facts andopinions that favour their side of the case. The pathologistis independent, impartial, and objective, a witness for thecourt, not for either of the parties to the case. This is an austere, and some might say self-righteous, belief, but I thinkit is the correct one.This is the ethos and attitude in which I believe. I have triedto practise and teach this principle all my professional lifeand to swim against the strong current that endeavours toinvolve me as an adversary. This is not easy when the Crownand defence counsel are clearly adversaries. Other pathologists have adopted the opposite view and consciouslyaccepted their recruitment to a “team,” most commonly thatof the Crown and the prosecution. The perception of the independent and impartial expert may be diminished whenthe first contact with the legal system, that is, the receipt ofa subpoena, is to appear as a witness for either the defenceor Crown. In the official view, the witness is believed capableof giving evidence to support one side of the case or the

other. For the pathologist, this most commonly means forthe prosecution, and any notion of impartial objectivity canbe firmly squashed at the outset.It would make things far easier for the pathologist if he orshe were summoned by the court, rather than by one side ofthe case or the other. I understand that this possibility isopen, but I have never known it used. Its use would not, andshould not, prevent the subpoena of other expert witnessesby the opposing sides to the case, particularly where evidence is of opinion and interpretation rather than of fact;but it would endorse the ideas of independence, non-partisanship, and objectivity that I believe to be integral tothe expert. However, in practical terms, and from my experience, I think this is most unlikely to happen. The adversarial attitude is too deeply ingrained in the law andthe thinking of lawyers. The best that we can hope for is thatpathologists educated in the requirements of the criminaljustice system will practise in the manner and in the beliefsthat I have suggested are correct and manage to resist theforces propelling them into the adversarial attitude, as wellas the temptations of its adoption.There is one risk that the pathologist as witness will continueto run under any system, and that is of perceiving himselfor herself as the righter of wrongs, the crusader for thedowntrodden, the knight on the white charger standing fortruth and justice against evil and oppression. This is a headyintoxicant and as dangerous as all intoxicants taken at thewrong time in the wrong place. It may well lead in shortorder to domination of opinion over fact, wilful distortionof evidence, and the attempted imposition of one’s ownjudgment over that of the court. I would be the last personto suggest that courts, judges, and juries are infallible, butthey are less fallible than individual judgment fortified by astiff dose of self-delusion. The pathologist as witness needsa mastery of the facts, an admission of where the facts arepartly known or unknown, an absolute differentiation between fact and opinion, and an ultimate capacity to admithis or her own limitations – “I do not know.” In almost 50years in the part-time practice of forensic pathology, I cancount on my fingers the cases into which I have gone feelingthat I had a duty to try to prevent a miscarriage of justice orto rectify injustice where it had been caused by poor pathology. What I think we should do, I have tried to spellout above, as a pragmatic creed forged on the anvil of hardexperience.

EMSON


Lymphomas of the Breast:A Clinicopathological Study Over 12 Years

Monalisa Sur, MBBS, FCPath, MMed, FRCPath, FRCPC, Prashant K. Dhamanaskar, and Leela Elavathil are members of theDepartment of Pathology and Molecular Medicine at McMaster University, Hamilton, Ontario. Noori Akhtar-Danesh, MSc,PhD, is a member of the School of Nursing and the Department of Clinical Epidemiology and Biostatistics at McMaster University. Monalisa Sur can be contacted at [email protected]. This article was peer reviewed.

Monalisa Sur, MBBS, FCPath (SA), FRCPath (UK), FRCPC, Prashant K. Dhamanaskar, MBBS, MD, FRCPC, Noori Akhtar-Danesh, MSc, PhD (Newcastle), Leela Elavathil, MD, FRCPC

ABSTRACTNon-Hodgkin’s lymphomas of the breast are rare and represent 0.04–0.50% of malignant lesions of the breast. Most cases are of a B-cell phenotype and are more commonly identifiedon the right side. This series summarizes our experience at a regional cancer centre over thepast 12 years with all cases of lymphoma of the breast based on the World Health Organization(WHO) 2008 classification. We analyzed the clinicopathological and immunophenotypical characteristics of 40 breast lymphomas and the relative frequency of primary versus secondarylymphomas. Statistical analysis of survival data based on disease progression, frequency of primary versus secondary origin, and subtype in the WHO classification were also assessed. In our series of 40 breast lymphomas, primary lymphoma was more common (63%) than secondary lymphoma (37%). Involvement of the right breast (63%) was significantly more frequent than that of the left breast (35%). Only one case of T-acute lymphoblastic lymphoma(T-ALL) showed bilateral breast involvement. Overall, B-cell lymphomas constituted the majority of lymphomas (88%). Diffuse large B-cell lymphoma (DLBCL) was the most commonsubtype (40%), followed by MALT lymphoma and follicular lymphoma (20% each). B-chroniclymphocytic lymphoma/leukemia constituted only 5% of the lesions. DLBCL was the most common subtype of both primary and secondary lymphomas. Rarer subtypes (20%) includednasal natural killer/T-cell lymphoma, T-ALL, B-acute lymphoblastic lymphoma, peripheral T-cell lymphoma, and anaplastic large-cell lymphoma. The overall 5-year and 10-year survivalrates were 78% and 67%, respectively. In our series, patients with secondary lymphoma involving the breast and those with high-grade histology fared worse than those with primaryinvolvement and low-grade histology. Thus, the histological subtype, type of involvement (primary versus secondary), and stage of the disease affected the survival of these patients. Allthese factors should be taken into consideration in the management of breast lymphomas.

RÉSUMÉLes lymphomes non hodgkiniens du sein sont rares et représentent de 0,04 à 0,5 % des lésions malignes du sein. La plupart des cas présentent un phénotype de lymphocytes B et sont dépistésle plus souvent du côté droit. Cette série résume notre expérience des douze dernières annéesdans un centre régional de cancérologie, où tous les cas de lymphomes du sein ont été identifiésd’après la classification de 2008 de l’Organisation mondiale de la Santé (OMS). Nous avonsanalysé les caractéristiques clinico-pathologiques et immunophénotypiques de 40 lymphomesdu sein et la fréquence relative des lymphomes primitifs par rapport aux lymphomes secondaires. Nous avons aussi effectué des analyses statistiques des données de survie, et ce, enfonction de la progression de la maladie, de la fréquence de l’origine primitive et de l’originesecondaire, et du sous-type (d’après la classification de l’OMS).

ORIGINAL ARTICLE


Dans la série de 40 lymphomes du sein, le lymphome primitif était plus fréquent (63 %) que le lymphome secondaire (37 %). L’atteinte du sein droit (63 %) était beaucoup plus fréquenteque celle du sein gauche (35 %). Seulement un cas de lymphome lymphoblastique aigu à cellulesT (LLA-T) présentait une atteinte bilatérale des seins. Dans l’ensemble, les lymphomes à cellulesB constituaient la majorité des lymphomes (88 %). Le lymphome diffus à grandes cellules B(LDGCB) était le sous-type le plus fréquent (40 %), suivi du lymphome de type MALT et dulymphome nodulaire (20 % chacun). Le lymphome ou la leucémie lymphocytique chroniqueà cellules B constituait seulement 5 % des lésions. Le LDGCB était le sous-type le plus fréquentdes lymphomes primitifs et secondaires. Le lymphome T/NK nasal, le LLA-T, la leucémie aiguëlymphoblastique à cellules B, le lymphome T périphérique et le lymphome anaplasique àgrandes cellules représentaient des sous-types plus rares (20 %). Les taux de survie cinq ans etdix ans après le diagnostic étaient respectivement de 78 % et de 67 %. Dans notre série, les patientes atteintes d’un lymphome secondaire du sein et celles dont l’examen histologique montrait un degré élevé de malignité s’en sont moins bien sorties que celles atteintes d’un lymphome primitif ou dont l’examen histologique montrait un faible degré de malignité. Ainsi,on constate que le sous-type histologique, le type d’atteinte (primitif ou secondaire) et le stadede la maladie ont une incidence sur la survie de ces patientes. Tous ces facteurs doivent être prisen considération dans la prise en charge des lymphomes du sein.

Non-Hodgkin’s lymphomas (NHLs) of the breast are rare

and represent 0.04–0.50% of malignant lesions of the

breast; they account for 1.7 to 2.2% of extranodal NHLs and

0.38% of all NHLs.1–5 Most cases are of the B-cell phenotype,

and they more commonly occur in the right breast.6 Primary

lymphomas have been defined by the criteria of Wiseman and

Liao.7 This series summarizes our experience of lymphoma of

the breast based on the World Health Organization (WHO)

classification at our regional cancer centre over the past 12

years.8 We analyzed the clinicopathological and immunophe-

notypic characteristics of the breast lymphomas and the relative

frequency of primary versus secondary lymphomas. Survival

data based on disease progression, frequency of primary versus

secondary origin, and type of lymphoma were also assessed.

Materials and MethodsWe searched through the Hamilton Health Sciences Anatomical

Pathology Department database (Meditech) using the key

words breast, lymphoma, and lymphoproliferative disorder and

retrieved 40 cases (original slides and blocks) of breast

lymphomas from 1993 to 2005. Clinical follow-up and survival

data were obtained for 37 cases from health records from the

Juravinski Cancer Centre. Primary breast lymphomas were

defined according to the criteria of Wiseman and Liao7:

1. Technically adequate pathological specimens

2. Mammary tissue and lymphomatous infiltrate in close

association

3. No evidence of concurrent widespread disease other than

ipsilateral axillary nodes occurring concomitantly with the

primary breast lesion

4. No prior diagnosis of extramammary lymphoma

Cases that did not fulfill the above criteria and had a prior

diagnosis of extramammary lymphoma were reclassified

as secondary lymphomas. A breast pathologist and a

hematopathologist independently reviewed the original slides

according to the WHO 2008 Classification of Tumours of

Haematopoietic and Lymphoid Tissue, and a consensus

diagnosis was taken in cases of discrepancy. An immunohisto-

chemistry panel (Table 1) was performed where relevant on

formalin-fixed, paraffin-embedded tissue sections using the

standard labelled streptavidin biotin (LSAB) technique.

SUR ET AL.


LYMPHOMAS OF THE BREAST: A CLINICOPATHOLOGICAL STUDY OVER 12 YEARS

Antibody Manufacturer Dilution Antigen Retrieval Clone

ALK-1 Novocastra 1/500 Citrate, HIER 5a4

CD3 Cell Marque 1/500 Citrate, HIER Rabbit

CD4 (OPD4) Dakocytomation 1/300 Citrate, HIER OPD4

CD5 Novocastra 1/50 Citrate, HIER 4C7

CD7 Dakocytomation 1/40 Dako lo, HIER CBC.37

CD8 Dakocytomation 1/100 Citrate, HIER C8/144B

CD10 Novocastra 1/25 Citrate, HIER 56C6

CD15 BD Pharmingen 1/50 Citrate, HIER LeuM1

CD20 Dakocytomation 1/100 None L26

CD21 Dakocytomation 1/200 Proteinase K 1F8

CD23 Novocastra 1/50 Dako lo, HIER 1B12

CD34 Novocastra 1/50 None QBend10

CD43 Dakocytomation 1/1,000 Citrate, HIER DF-T1

CD45 Dakocytomation 1/200 None 2B11/PD7/26

CD56 Novocastra 1/50 Dako lo, HIER 1B6

CD30 Dakocytomation 1/30 Citrate, HIER BerH2

CD79A Dakocytomation 1/100 Citrate, HIER HM57

CD138 Biocare 1/40 Citrate, HIER B-A38

BCL2 Dakocytomation 1/25 Citrate, HIER 124

BCL6 Dakocytomation 1/50 Dako Hi, HIER PG-B6p

CYCLIN D1 LabVision 1/75 Dako lo, HIER SP4 (rabbit)

Ki67 Dakocytomation 1/1,000 Citrate, HIER MIB-1

MYELOPX Dakocytomation 1/1,000 None Rabbit

TDT Novocastra 1/25 Dako lo, HIER SEN28

Table 1. Antibody Panel Used for Diagnosis and Classification

HIER = heat-induced epitope retrieval.

For statistical analysis, cases were divided into low-grade lesions (follicular lymphoma [FL], B-chronic lymphocyticlymphoma/leukemia [B-CLL], and MALT lymphoma) andhigh-grade lesions (diffuse large B-cell lymphoma[DLBCL], acute lymphoblastic lymphoma [ALL], periph-eral T-cell lymphoma [PTCL], natural killer/T-cell lym-phoma [NK-T lymphoma], and anaplastic large-celllymphoma [ALCL]). Statistical analysis was conductedusing the Kaplan-Meier curve followed by log-rank test foroverall survival, primary versus secondary cases, and high-grade versus low-grade lesions. Cox regression analysis wasconducted to compare survival time between primary andsecondary lymphomas and between low- and high-grade lesions. Because of the small sample size, we depicted Kaplan-Meier curves for only primary versus secondarycases, and high-grade versus low-grade lymphomas. Also,

to increase the power of the test, Cox regression analysis wasconducted to compare hazard ratio (HR) between primaryand secondary lymphomas and between low- and high-grade lesions.

ResultsAll cases were reviewed and reclassified according to theWHO 2008 classification; only four cases needed revisionof diagnostic nomenclature. One case of DLBCL was reclassified as primary MALT lymphoma of the breast. Twoother cases were reclassified as MALT lymphoma from the initial diagnoses of B-chronic lymphocyticlymphoma/leukemia (B-CLL/small lymphocytic lymphoma[SLL]) and lymphoplasmacytic lymphoma. One case ofMALT lymphoma was reclassified as atypical B-CLL/SLL.The major clinical and histopathological features of the


SUR ET AL.

Table 2. Clinical Characteristics of Breast Lymphoma

Characteristic Findings

Number of cases 40

Type of involvement Primary: 25 (63%)

Secondary: 15 (37%)

Sex All females

Laterality Left: 14 (35%)

Right: 25 (63%)

Bilateral: 1

Age Range: 34–86 y

Mean: 60 y

Clinical presentation Palpable mass (38/40 cases)

Screening mammogram/sonogram (2/40 cases);

both primary, 1 MALT lymphoma, 1 B-CLL/SLL

Association 2/40 cases presented with mass during pregnancy – both primary DLBCL

1 patient with FL had concurrent plasma cell myeloma

1 patient with FL had concurrent infiltrating duct carcinoma

Phenotype B-cell phenotype: 35 (88%)

T-cell phenotype: 4 (10%)

Natural killer/T-cell phenotype: 1 (2%)

Bone marrow staging Positive: 7 (18%) (2/25 primary, 5/15 secondary)

Negative: 33 (82%)

Follow-up duration Range: 4 mo–10 y

Follow-up status Dead from disease progression: 10 (25%)

Dead from unrelated disease: 9 (23%)

Alive with complete remission: 18 (45%)

Alive with disease: 3 (7%)

B-CLL = B-chronic lymphocytic lymphoma; FL = follicular lymphoma; SLL = small lymphocytic lymphoma.

cases are summarized in Tables 2 and 3. DLBCL (Figure 1)was the most commonly encountered subtype (40%), followed by FL and MALT lymphoma (Figure 2), each constituting 20% of the breast lymphomas. The rarer subtypes accounted for the remaining 20% of the lymphomas (Table 4; Figure 3). Most cases of DLBCLdemonstrated centroblastic morphology, with two cases

showing immunoblastic and one case showing anaplasticmorphology. Ten cases of DLBCL were of germinal centreB cell like (GCB) phenotype, and six cases showed non-GCBphenotype by immunohistochemistry. Two cases of eachwere secondary to the breast. The proliferation index, basedon Ki67 expression, ranged from 40 to 75%.



Table 3. Histopathological Types of Lymphoma

Histopathological Type Total (%) Primary Secondary

Diffuse large B-cell lymphoma 16 (40) 12 4MALT lymphoma 8 (20) 7 1Follicular lymphoma 8 (20) 1 7B-chronic lymphocytic lymphoma/leukemia 2 (5) 2 0T-acute lymphoblastic lymphoma 2 (5) 0 2B-acute lymphoblastic lymphoma 1 (2.5) 1 0Anaplastic large cell lymphoma 1 (2.5) 1 0Nasal type natural killer/T-cell lymphoma 1 (2.5) 0 1Peripheral T-cell lymphoma 1 (2.5) 1 0Total 40 25 15

Figure 1. Diffuse large B-cell lymphoma of the breast. (Hematoxylin and eosin, originalmagnification 200x)

Figure 2. MALT lymphoma of the breast. (Hematoxylin and eosin, original magnification200x)

Table 4. Rare Lymphoma Types Involving Breast

Histopathological Type Age (y) Primary or Secondary Recurrence Follow-Up StatusNasal type natural killer/T-cell lymphoma 51 Secondary Progression DOD – 12 moT-acute lymphoblastic lymphoma 54 Secondary Axillary LN, DOD – 15 mo

local breastT-acute lymphoblastic lymphoma 40 Secondary Nil CR – 3 yPeripheral T-cell lymphoma 41 Primary Nil CR – 7 yB-acute lymphoblastic lymphoma 69 Primary Nil CR – 4 moAnaplastic large cell lymphoma 71 Primary Nil CR – 5 y

CR = alive with complete remission; DOD = dead from disease; LN = lymph node.


SUR ET AL.

Figure 3. Rare lymphoma types involving breast (Hematoxylinand eosin, original magnification 200x)A, Anaplastic large cell lymphoma. B, B-acute lymphoblasticlymphoma. C, Natural killer/T-cell lymphoma. D, Peripheral T-cell lymphoma.

For the secondary lymphomas, lymph nodes were the main sitesof initial involvement, with extranodal sites such as the stomach,spleen, ovary, mediastinum, and nasal cavity in a few cases. Atthe time of diagnosis of breast lymphoma, seven patients (18%)had bone marrow involvement (stage IV disease). Two of these patients had primary low-grade breast lymphoma: MALT lymphoma and B-CLL/SLL. The remaining five cases with bonemarrow involvement had secondary breast involvement byDLBCL (1), MALT lymphoma (1), and FL (3). The initial diagnosis of primary DLBCL was made at mastectomy in threepatients. One patient with secondary DLBCL was treated withmastectomy and local radiotherapy (RT). Most patients weretreated with CHOP (cyclophosphamide, doxorubicin, vin-cristine, and prednisone) or a CHOP-like chemotherapy, withadditional local RT in six patients. Local RT alone was given innine patients who had low-grade lymphoma localized to thebreast.

A total of 19 patients died during the follow-up period, 10 from

disease progression and nine from unrelated diseases. The 10

patients who died from disease progression had survival periods

ranging from 5 months to 7 years (median 19.5 months, mean

30.8 months). Eight of these patients had high-grade lymphoma:

DLBCL in six, nasal NK-T lymphoma in one, and T-acute

lymphoblastic lymphoma/leukemia (T-ALL) in one. Two patients

had a low-grade lymphoma (FL and MALT lymphoma). The

survival in these patients with high-grade lymphoma ranged from

5 months to 3 years (median 13.5 months, mean 19 months), and

those with low-grade lymphoma survived for 6 and 7 years,

respectively. Thus, histopathological type had a marked impact

on the duration of survival. In the patients who died from their

disease, three received chemotherapy and RT, three underwent

mastectomy with one getting receiving RT, and four received

chemotherapy alone. Of this group, seven patients had secondary

breast involvement and two had primary involvement. This group

showed recurrence in nodal and extranodal sites with large cell

transformation in one and disease progression at the same site in

two patients.

Nine patients died from unrelated disease, and all were in

complete remission. Only two of these had regional lymph node

recurrence, but they were treated successfully. The patients were

A

C

B

D



disease free from 1 to 10 years (median 60

months, mean 55.6 months). Eighteen patients

showed complete remission and were still alive

at the last follow-up. Thirteen patients had

primary while five patients had secondary breast

involvement. DLBCL was the most common

subtype followed by FL and MALT lymphoma.

The other subtypes in this group included one

case each of PTCL, ALCL, T-ALL, and B-ALL.

Eight patients received local RT, seven

received chemotherapy, and three received

chemotherapy alone. The follow-up period

ranged from 4 months to 9 years in this group

(median 72 months, mean 62.4 months). Three

patients were alive with disease after a follow-up

of 4 months, 6 years, and 9 years, respectively

(mean 16 months). All three lymphomas were

low grade.

In our case series, the 5-year survival was 78%

and 10-year survival was 67% by Kaplan Meier

curves. Mean survival time was 7.90 years (SD =

0.60 and CI 95% 6.71–9.08). Based on the uni-

variate analysis, there was marginally significant

difference in the survival time between primary

and secondarylymphomas (Log rank test = 3.52,

p = .061) (Figure 4). There were significant

differences in survival in patients with high-

grade versus low-grade lymphomas (Log rank

test = 3.72, p = .05) (Figure 5). Survival analysis

conducted using the Cox regression technique

(multivariate) indicated that both the grade of

the lesion and the type of involvement (primary

versus secondary) had significant effects on the

HR of death. pValues for the effect of grade and

primary versus secondary were .033 and .029,

respectively, and HRs were 5.8 (CI 95% =

1.15–29.08) and 4.8 (CI 95% = 1.17–19.61),

respectively. This implies that the risk of death

from the disease in patients with a high-grade

lesion is about 5.8 times greater than that of

patients with a low-grade lesion. Similarly, the

risk of death fromsecondary lymphoma is about

4.8 times that of primary lymphoma.

Primary lymphomaSecondary lymphomaPrimary lymphoma-censoredSecondary lymphoma-censored

1.0

0.8

0.6

0.4

0.2

0.0

0.00 2.00 4.00 6.00 8.00 10.00

Survival Functions

Time (year)

Cum

ulat

ive

Sur

viva

l

High grade lymphomaLow grade lymphomaHigh grade lymphoma-censoredLow grade lymphoma-censored

1.0

0.8

0.6

0.4

0.2

0.0

0.00 2.00 4.00 6.00 8.00 10.00

Survival Functions

Time (year)

Cum

ulat

ive

Sur

viva

l

Figure 5. Kaplan-Meier survival curves for breast lymphomas of high and low grade.

Figure 4. Kaplan-Meier survival curves for primary and secondary lymphomas of the breast.


SUR ET AL.

DiscussionBreast lymphomas are rare (0.04–0.05%) and account for

1.7–2.2% of extranodal lymphomas and 0.38% of all

NHLs.1–5 In our study, all patients were females, with an age

range of 34–86 years (mean 60 years). This finding is similar

to previously reported series in which the peak age incidence

was usually the sixth decade.9–11 Based on the criteria of

Wiseman and Liao,7 25 were primary (63%) and 15 were

secondary (37%) lymphomas of the breast. Other studies

have reported slightly more secondary lymphomas than

primary lymphomas of the breast.12,13 The right breast was

involved in 25 patients and left breast in 14 patients; one case

showed bilateral involvement by a secondary T-ALL. This

tendency to right breast preponderance has been reported

previously and remains unexplained.6,7,12,14 In 15% of cases,

breast lymphomas may occur during pregnancy or

lactation.15 In this series, two cases presented with a breast

mass during pregnancy. Both patients were diagnosed with

primary DLBCL and were treated with chemotherapy and

local radiation after successful completion of pregnancy.

Both patients are alive and in complete remission with a

follow-up period of 4 and 9 years, respectively. The majority

of our patients (38/40) presented with a palpable mass.

In two patients, the lymphoma was detected by

mammogram/sonogram during breast screening and was

diagnosed histopathologically as primary MALT lymphoma

and B-CLL/SLL, respectively. There are no specific

radiological features that would suggest a diagnosis of

lymphoma over breast carcinoma, and mammographic

findings vary from a discrete mass with marginal spiculation

to a diffuse increase in parenchymal density.16,17

Most primary breast lymphomas are of B-cell phenotype.

Primary T-cell lymphoma of the breast is uncommon,

accounting for 3% of all cases.12,15,18 In our series, 88% were

of B-cell phenotype, 10% were of T-cell phenotype, and 2%

of NK-T-cell phenotype. Overall, DLBCL was the most com-

mon subtype (40%), followed by FL and MALT lymphoma

(20% each) and B-CLL/SLL (5%). Many series have re-

ported a predominance of DLBCL,12,15,18,19 with the incidence

of follicular lymphoma ranging from 0 to 66%.9,20,21 There

is one case series in which primary MALT lymphoma of the

breast was the most common subtype, comprising 64.3%,22

and MALT lymphoma has been reported in other series with

a frequency ranging from 0 to 44%.12,13,15,18,23 Although a de-

finitive cause for the increased incidence of MALT lym-

phoma in some case series is not apparent, geography may

have an unexplained role. Twenty percent of our cases were

rare subtypes that included T-ALL with bilateral breast

involvement, NK-T lymphoma, B-ALL, ALCL and PTCL

(see Table 3). The first two patients with secondary

involvement of the breast from other extranodal sites died

of disease within 15 and 12 months. The latter three patients

had primary involvement of the breast and remain in

complete remission after treatment. The series of T-cell

lymphomas of the breast reported by Aguilera et al. (two

PTCLs, one ALCL, and one NK-T lymphoma) suggested

that these tumours have an aggressive clinical course.24

Another interesting feature of our series was the absence of

central nervous system (CNS) dissemination; in other series,

CNS involvement ranged from 2 to 27%.11,15,25–27 While the

reason for this difference is unclear, it is possible that cases

in our series were diagnosed earlier and treated more

aggressively. Clinicians should be aware of the possibility of

CNS spread in patients with breast lymphoma, and

diagnostic imaging of the brain should be performed if

patients develop neurological symptoms. CNS prophylactic

treatment is controversial, and it is recommended that

patients be followed up closely for signs and symptoms of

CNS relapse and not be given prophylaxis routinely.

In our study, most of the primary lymphomas were stage I,

with only two cases showing bone marrow involvement at

the time of initial diagnosis. All secondary lymphomas were

stage III or IV. Most patients received chemotherapy with or

without local RT, with four undergoing mastectomy. The

5-year survival was 78%, and 10-year survival was 67% by

Kaplan-Meier curves. Mean survival time was 7.90 years (SD

= 0.60 and CI 95% = 6.71–9.08). These results show a

distinct improvement in survival time when compared with

the initial report of Wiseman and Liao in 1972, which

suggested a poor prognosis for patients with breast

lymphoma treated with surgery with or without RT. In that

series, the longer survivors received a radical mastectomy

and RT.7 In a series from the Mayo Clinic by Wong et al., the

5-year survival rate was 70%, and the relapse-free

survival rate survival rate was 42%.26 In other published

series, the 5-year survival rates for patients with stage I



disease ranged from 61 to 89% compared with 0 to 50% for

stage II disease.11,15,18,27–31 In the series by Vigliotti et al., the

10-year survival rate was 71% and compared favourably

with most reported series including patients treated with

chemotherapy, RT, or both.32 In a review of 380 cases

reported from 1950 to 2002 in Japan, the findings

regarding age, laterality, and histological subtype were

similar to those in other reported series.33 The 5-year

survival rate of breast NHL was 37.6% among all cases,

urvival declining with advancing stage of disease. The

authors also stated that minimum surgery for histological

diagnosis was necessary for therapeutic planning and to

determine prognosis in the treatment of the primary breast

NHL. A more recent large study by Talwalkar et al. classified

breast lymphomas using the WHO 2008 classification and

divided the lymphomas into localized and disseminated

groups.34 DLBCL was the most common in the localized

group, with FL being the most common in the disseminated

group. In their series, there was a significant difference in

the disease-free survival between localized and disseminated

DLBCL (p = .003). DLBCL in the disseminated group had a

worse disease-free survival compared with that of FL or

MALT lymphoma in the same group.34 In our series, patients

with secondary breast lymphoma and high-grade histology

fared worse than those with primary involvement and

low-grade histology.

In the diagnosis and management of breast lymphomas,

strict criteria should be used to determine whether the

lymphoma is primary or secondary since this impacts

overall survival. Breast lymphomas should be graded and

subclassified based on the WHO 2008 classification, and

hematopathological consultation should be obtained. Our

study confirms that histological subtype, type of

involvement (primary versus secondary), and stage of

disease affect the survival rate and should be taken into

consideration.

References1. Eskelinen M, Collan Y, Puittinen J, et al. Lymphoma of the breast.

Ann Chir Gynaecol 1989;78:149–52.2. Misra A, Kapur BM, Rath GK. Primary breast lymphoma.

J Surg Oncol 1991;47:265–70.3. Vianello F, Sgarabotto D, Stefani PM, et al. Primary breast lymphoma.

Forum (Genova) 1998;8:188–95.4. Babovic N, Jelic S, Jovanovic V. Primary non-Hodgkin’s lymphoma

of the breast. Is it possible to avoid mastectomy? J Exp Clin Cancer Res 2000;19:149–54.

5. Jeon HJ, Akagi T, Hoshida Y, et al. Primary non-Hodgkin’s malignant lymphoma of the breast. An immunohistochemical study of seven patients and literature review of 152 patients with breast lymphoma in Japan.Cancer 1992;70:2451–9.

6. Brogi E, Harris NL. Lymphomas of the breast: pathology and clinical behavior.Semin Oncol 1999;26:357–64.

7. Wiseman C, Liao KT. Primary lymphoma of the breast. Cancer 1972;29:1705–12.

8. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

9. Mambo NC, Burke JS, Butler JJ. Primary malignant lymphomas of the breast.Cancer 1977;39:2033–40.

10. Schouten JT, Weese JL, Carbone PP. Lymphoma of the breast. Ann Surg 1981;194:749–53.

11. Ha CS, Dubey P, Goyal LK, et al. Localized primary non-Hodgkin’s lymphomaof the breast. Am J Clin Oncol 1998;21:376–80.

12. Cohen PL, Brookes JJ. Lymphomas of the breast: a clinicopathologic and immunohistochemical study of primary and secondary cases. Cancer 1991;67:1359–69.

13. Topolovski M, Crisan D, Mattson JC. Lymphoma of the breast: a clinicopathologic study of primary and secondary cases. Arch Pathol Lab Med 1999;123:1208–18.

14. Lamovec J, Jancar J. Primary malignant lymphoma of the breast: lymphoma of the mucosa-associated lymphoid tissue. Cancer 1987;60:3033–41.

15. Hugh JC, Jackson FK, Hanson J, et al. Primary breast lymphomas: an immunohistologic study of 20 new cases. Cancer 1990;66:2602–11.

16. Meyer JE, Kopans DB, Long JC. Mammographic appearance of malignant lymphoma of the breast. Radiology 1980;135:623–6.

17. Paulus DD. Lymphomas of the breast. Radiol Clin Noth Ann 1990;66:2602–11.

18. Arber DA, Simpson JF, Weiss LM, et al. Non-Hodgkin’s lymphoma involvingthe breast. Am J Surg Pathol 1994;18:288–95.

19. Giardini R, Piccolo C, Rilke F. Primary non-Hodgkin’s lymphomas of the female breast. Cancer 1992;69:725–35.

20. Lieberman L, Giess C, Dershaw DD, et al. Non-Hodgkin’s lymphoma of the breast: imaging characteristics and correlation with histopathologic findings. Radiology 1994;192:157–60.

21. Mattia AR, Ferry JA, Harris NL. Breast lymphoma: a B-cell spectrum including the low grade B-cell lymphoma of mucosa associated lymphoid tissue. Am J Surg Pathol 1993;17:574–87.

22. Pedro F, Saudade A, Cabecadas J, et al. High frequency of MALT lymphoma in a series of 14 cases of primary breast lymphoma. Appl ImmunohistochemMol Morphol 2002;10:115–20.

23. Domechek SM, Hecth JL, Fleming MD, et al. Lymphomas of the breast: primary and secondary involvement. Cancer 2002;94:6–13.

24. Aguilera NSI, Fattaneh A, Tavassoli F, et al. T-cell lymphoma presenting in the breast: a histologic, immunophenotypic and molecular genetic study of four cases. Mod Pathol 2000;13:599–605.

25. Au WY, Chan ACL, Liang R. Lymphoma of the breast in Hong Kong Chinese.Hematol Oncol 1997;15:33–7.

26. Wong WW, Schild SE, Halyard MY, et al. Primary non-Hodgkin’s lymphomaof the breast: the Mayo Clinic experience. J Surg Oncol 2002;80:19–25.

27. Gholam D, Bibeau F, Bosq J, et al. Primary breast lymphoma. Leuk Lymphoma 2003;44:1173–8.

28. Abbondanzo SL, Seidman JD, Lefkowitz M, et al. Primary diffuse large B-celllymphoma of the breast. A clinicopathologic study of 31 cases. Pathol Res Pract 1996;192:37–43.

29. Brustein S, Filippa DA, Kimmel M, et al. Malignant lymphomas of the breast.A study of 53 patients. Am Surg 1987;205:144–50.

30. Liu FF, Clark RM. Primary lymphoma of the breast. Clin Radiol 1986;37:567–70.

31. DeBlasio D, McCormick B, Straus D, et al. Definitive irradiation for localizednon-Hodgkin’s lymphoma of the breast. Int Radiat Oncol Biol Phys 1989;17:843–6.

32. Vigliotti ML, Dell’olio M, La Sala A, Di Renzo N. Primary breast lymphoma:outcome of 7 patients and a review of the literature. Leuk Lymphoma 2005;46:1321–7.

33. Masaya U, Yukimasa M, Yoshio G, et al. Primary non-Hodgkin’s lymphoma of the breast: report of a case with special reference to 380 cases in the Japaneseliterature. Breast Cancer 2005;12:154–8.

34. Talwalkar SS, Roberto NM, Jose RV, et al. Lymphomas involving the breast: astudy of 106 cases comparing localized and disseminated neoplasms. Am J Surg Pathol 2008;32:1299–309.


ABSTRACTRegenerative medicine aims to restore diseased or damaged tissues of the body and, as such, is

the ultimate form of personalized medicine. Cells, scaffolds, and tissue integration together

with vascularization are fundamental to the success of this approach. This review provides a

synopsis of the current strategies and challenges for regenerative medicine using the nucleus

pulposus, a tissue present in the intervertebral disc, as an example. The pathologist may one

day be required to provide tissues or cells to facilitate this treatment approach.

RÉSUMÉLa médecine régénératrice a pour but de remplacer les tissus malades ou endommagés; en ce

sens, elle représente la forme ultime de la médecine personnalisée. Cellules, supports, implan-

tation tissulaire et vascularisation en sont les éléments fondamentaux. L’article de fond offre

un aperçu des stratégies et des défis actuels dans l’utilisation du noyau gélatineux, présent dans

le disque intervertébral, en médecine régénératrice, à titre d’exemple. Le pathologiste sera peut-

être un jour celui qui fournira les tissus ou les cellules nécessaires à la médecine régénératrice.

ORIGINAL ARTICLE

Tissue Engineering the Nucleus Pulposus:Is It Feasible?

Emma V. Dare, PhD, and Rita A. Kandel, MD, are members of the Canadian Institutes of Health Research Bioengineering ofSkeletal Tissues Team, and the Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University ofToronto, Toronto, Ontario. Rita Kandel can be contacted at [email protected] article was peer reviewed.

Regenerative medicine is an emerging field that

combines many disciplines, including cell and

molecular biology, engineering, polymer science, and

clinical medicine, with the goal of regenerating diseased or

damaged tissues and organs in the body.1 The aim is not only

to replace the tissue that is malfunctioning but to

provide a replacement that stimulates and supplies elements

necessary for the body’s natural repair mechanisms.2 It has

been estimated by the U.S. National Academy of Science that

more than a hundred million patients in the United States

with conditions such as cardiovascular disease, autoimmune

diseases, diabetes, cancer, neurodegenerative diseases,

arthritis, and burns could benefit from regenerative

medicine strategies.3 Importantly, this approach will obviate

the need for surgery or the use of drugs, with all their

potential side effects.

To regenerate a tissue, a number of different approaches may

be taken. Acellular scaffolds, which rely on and direct cell

ingrowth from the surrounding tissues, can be implanted.4

Alternatively, cells alone5 or combined with a carrier such as

a scaffold or hydrogel can be used.6 When cells are used for

tissue regeneration, a cell source must be identified. Cells

may be obtained from either a biopsy of donor tissue or a

bone marrow aspirate, although other options are currently

being developed. The cells must be expanded and then either

differentiated in culture and injected back into the host or

seeded onto a scaffold and implanted before or after in vitro

culture (Figure 1). Culture in vitro allows for tissue

formation prior to implantation, a feature that may be

critical for rapid integration and function after

implantation. The cells can be from a source that is

heterologous (different species), allogeneic (same species but

different individual), or autologous (same individual). The

use of xenogeneic or allogeneic cells is controversial.

Autologous cells are ideal as they do not incite an immune

response and thus avoid the complications associated with

Emma V. Dare, PhD, Rita A. Kandel, MD


TISSUE ENGINEERING THE NUCLEUS PULPOSUS:IS IT FEASIBLE?

immune-modulating drugs. Identifying a cell source for an

organ that has multiple components – such as the heart,

which has myocardiocytes, endothelium, pacemaker cells,

coronary arteries, and valves – is daunting. Integration and

vascularization add other levels of complexity. Clearly

regenerative medicine as a therapy is still in the early stages

of development. At present, it seems that tissues composed

of a single or at most two cell types – such as nucleus

pulposus (NP) or articular cartilage – and are avascular are

more likely to be the first tissues treated using this approach.

This review summarizes the current research into the

regeneration of the NP, a tissue present in the intervertebral

disc (IVD).

Figure 1. Depiction of the typical methods and goals of regenerative medicine.

The IVD and DegenerationLow back pain associated with IVD degeneration is the most

common cause of musculoskeletal disability.7 The etiology

of this disease is poorly understood. However, it is known

that the early changes occur in the NP, which is located in

the centre of the IVD and distributes hydraulic pressure in

all directions within the disc. The annulus fibrosus

surrounds the NP and consists of concentric lamellae of

collagen fibres that aid in load absorption and distribution.

The cartilage end plates mark the transition between the

IVD and the vertebra (Figure 2).8 The relationship between

the tight lattice of the annulus fibrosus and the semifluid NP

is important in providing the biochemical properties of IVD

necessary for spinal stability.9

Figure 2. Histological section of a human intervertebraldisc from a female fetus at 20 weeks’ gestation. Notochordal cells (NC) are located at the centre of the nucleus pulposus. Note that the annulus fibrosus is notvisible in this photograph. CEP = cartilage end plate.(Hematoxylin and eosin; bar = 100 µm)

The extracellular matrix of the NP consists mostly of

collagen type II10 and proteoglycans such as aggrecan11 and

versican.12 The cells of the NP are primarily small

chondrocyte-like cells with a possible second population of

notochordal cells, depending on the age and species.13

Notochordal cells can be distinguished from the NP cells

morphologically because they are larger and contain

vacuoles and are surrounded by myxoid matrix (Figure

3).13,14 The exact role that notochordal cells play in the

formation of the NP has not been fully elucidated.

Histologically, IVD degeneration is marked by disc thinning

and a merging of the annulus fibrosus and NP tissues. Cell

viability and proteoglycan and tissue water content all

decrease with an increasing degree of tissue degeneration in

the NP.15 Alterations in the NP cause the annulus fibrosus

Isolatestem/primary

cells

Harvest tissueor bonemarrow

Implant immediately into

patient

Implant evaluation• Integration and vascular in�ltration• Function• Immunogenicity

Inject cells backinto patient

Expand and/ordifferentiate cells

Seed cells into scaffoldor place onsubstrate

Culture constructin vitroImplant regenerated

tissue into patient

Regenerative Medicine


DARE AND KANDEL

to support more load, and the added stress can lead to tears,

bulging, rupture, and herniation of the disc.16 It is likely that

the avascular nature of the IVD compromises its ability to

repair the damage.17,18 Treatment options include the

surgical removal of disc material to alleviate nerve

impingement, fusion and internal fixation to stabilize

adjacent vertebrae, or disc replacement with a prosthesis.19,20

These treatments are not always successful and have the

potential for serious complications.21 It is evident that

there is a need for a more effective treatment for disc

degeneration, and a biological approach would be optimal

as it would preserve joint motion and allow for remodelling

in response to loading.

Figure 3. Monolayer culture of bovine nucleus pulposuscells. Vacuolated notochordal cells are indicated by white arrows. (Bar = 50 µm)

Tissue Engineering of the IVDAs the extracellular matrix of the NP is so important to its

function and physiological properties, regenerating an NP

that has the appropriate composition is critical. To

accomplish this, two issues must be addressed – the

scaffold/environment and the cells.

Scaffold MaterialsBiomaterials utilized in tissue engineering are important as

they are able to stimulate specific cellular responses at the

molecular level22 and can regulate cell and matrix

orientation. Biomaterials need to have certain characteristics

to be useful for tissue engineering.23,24 The biomaterial must

be biocompatible and biodegrade into nontoxic products at

the same rate as the tissue being regenerated. Scaffolds are

one type of biomaterial and are three-dimensional porous

structures. The scaffold should have a porous network to

allow for tissue ingrowth or formation and nutrient delivery.

The mechanical properties of the scaffold should be

sufficient to support functionality, which for orthopedic

applications would be weight bearing together with

mechanical stability and mobility.9 Natural polymers (e.g.,

collagen, fibrin, alginates, chondroitin sulphates, and

chitosan) and synthetic polymers (e.g., polyglycolide,

polylactide, and polyhydroxybutyrate) are just some of the

biomaterials that have been used for the regeneration of

musculoskeletal tissues.25 Synthetic polymers are of great

interest because they enable better control over the physical

and chemical properties of the scaffolds.26 For example, poly

(vinyl alcohol) hydrogels have been implanted as

acellular NP replacements into the lumbar IVD of

baboons.6 The implants were well tolerated over 24 months

in vivo; however, the extrusion (herniation) rate remained

high (20%). Natural materials have structures that more

often resemble the native tissue environment. Halloran et

al.27 created a scaffold composed of the macromolecules of

the native NP extracellular matrix, which appears to favour

NP tissue formation. The scaffold was composed of

enzymatically cross-linked atelocollagen (a water-soluble

form of collagen) type II with varying concentrations of

aggrecan and hyaluronan molecules present in the

extracellular matrix of the NP. Other materials can also be

used as substrates to support NP tissue regeneration.

Calcium polyphosphate, which is a bone substitute, has been

used for this purpose. NP tissue can be formed on and

integrated with the underlying substrate after seeding cells

on its top surface.28 The substrate, when placed into the

bone, is fixed in place by bony ingrowth. It is also possible

to induce repair by in situ injection of a material in the

absence of cells. Wang et al.29 implanted non-cell-based

materials into porcine discs in order to stimulate tissue

growth and increase the disc functional integrity. It was

found that discs with implanted gel-foam (absorbable

gelatin sponge) had the best integrity after 2 months.

Injection of platelet-rich plasma (containing growth factors)



encapsulated in gelatin microspheres, as an in situ

biomaterial scaffold, into the NP of degenerate rabbit IVDs30

slowed down the disease process as a result of the added

tissue structure, compared with results in animals that did

not receive the treatment.

Although there has been great progress in NP tissue

engineering, few in vivo implantation studies have been

performed to date. The optimal biomaterial that will induce

or support in situ regeneration of NP tissue has yet to be

identified.

Cell SourceAs well as the optimal scaffold for NP tissue engineering,

another important component of the system is the cells. One

of the major issues limiting the clinical application of

regenerative medicine is the identification of a cell source,

which has to be easily harvested and allow cell number

expansion before reimplantation. There are an estimated

4,000 cells/mm3 in the normal human NP.31,32 Expanding the

number of NP cells in culture to obtain sufficient numbers

for regeneration may result in de-differentiation of these

cells.33 It has also been shown that IVD cells can exhibit

cellular senescence, which may lead to altered phenotype

and proliferation.34 Although it is possible to isolate normal

cells from a non-degenerate disc, they may not be suitable

for use. For example, it has been shown that a

polymorphism (Trp2 allele) in the COL9A2 gene encoding

the alpha-2 chain of collagen IX can predispose an

individual to disc degeneration.35 Non-degenerate discs

from these individuals were found to be mechanically

inferior to non-degenerate normal discs from individuals

without the polymorphism,36 suggesting that the use of

genetically altered primary cells isolated from an otherwise-

healthy IVD may not be appropriate for the regeneration of

normal tissue.

For these reasons, many researchers have opted to use stem

cells for regeneration of the NP. Stem cells have the unique

capacity to generate progeny with the same developmental

potential (self-renew) or to differentiate into the lineages of

the stem cell’s tissue origin. Stem cells are generally classified

as pluripotent (embryonic stem cells [ESCs]) or multipotent

(somatic stem cells). Human ESCs are derived from the

epiblast cells of a blastocyst.37 ESCs can be readily grown as

undifferentiated cells under defined conditions, providing

an unlimited supply of pluripotent stem cells. While they

are capable of differentiating into all three germ layers of the

embryo – and, hence, all cell types of the human body –

there are many ethical issues associated with their

acquisition and use. Some examples of these include the

controversy of utilizing allogeneic cells for NP tissue

engineering, which may result in donor-host rejection as it

is controversial as to whether ESCs have immune-privileged

properties.38 In addition, the ability of residual implanted

undifferentiated ESCs to form teratomas, an unacceptable

complication for a treatment designed for a non-

life-threatening disease, is another possibility.

Alternatively, adult somatic stem cells, of which

mesenchymal stem cells (MSCs) are one type, may be a more

appropriate source of cells. These can differentiate into all

cells of mesenchymal lineage and can be readily harvested

from a number of tissues, such as bone marrow and fat.39

Importantly, they can be expanded in culture while retaining

their ability to differentiate. For example, studies have

verified that human bone marrow MSCs can maintain

their chondrogenic differentiation potential up to an

approximately 60,000-fold expansion of cell numbers.40

However, there are some limitations to the use of these cells

as their ability to proliferate can decrease with age and

disease.41 Nevertheless, studies have demonstrated the

feasibility of using MSCs for regeneration of NP tissue. Le

Maitre et al.42 injected human MSCs into bovine NP tissue

explants. They found that MSCs from older individuals

differentiated spontaneously into chondrocyte-like NP cells

upon insertion into NP tissue in vitro. MSCs have also been

cultured in chitosan-glycerophosphate hydrogels in vitro.43

After 4 weeks, the MSCs differentiated into cells with a

phenotype that was similar to NP cells; the cells secreted

proteoglycans and collagens in a ratio that closely resembles

that of NP cells. Autologous MSCs mixed in atelocollagen

have been shown to decelerate disc degeneration after

implantation into the degenerated discs of rabbits.44

Transplantation of MSCs alone into animals has also been

attempted for in situ regeneration of the NP. Sakai et al.45

found that injection of MSCs into degenerate rabbit IVDs

led to tissue regeneration after 24 weeks. In another study,

human MSCs were injected into lumbar discs of pigs either


DARE AND KANDEL

alone or with a PuraMatrix hydrogel carrier.46 After 6

months, the injected cells were detected in the disc,

confirming their survival; they also expressed typical

chondrogenic markers suggesting differentiation toward

disc-like cells. The results obtained from the use of MSCs

for NP regeneration, while encouraging, are still preliminary.

An alternate cell source may be inducible pluripotent stem

(iPS) cells, which can be generated by viral transfection of

the four transcription factors Oct4, Sox2, c-Myc, and Klf4

(Yamanaka factors) into somatic cells.47 Human fibroblasts,

for example, have been transfected successfully.48 These iPS

cells return to an undifferentiated, pluripotent state and are

indistinguishable from ESCs in morphology, proliferation,

gene expression, and their ability to form teratomas.48

Investigation of the specific signalling pathways activated

following transfection of the Yamanaka factors have49 shown

that Oct4 and Sox2 are core factors, Klf4 enhances the core

factors for development regulation, and c-Myc plays a role

in regulating metabolism. These factors were found to

regulate at least 14 crucial developmental signalling

pathways to maintain ESC pluripotency.49 In addition, a new

technology using virus-independent, transposon-mediated

reprogramming of somatic cells into iPS cells has

been developed,50 eliminating one of the potential

contraindications to the clinical use of these cells. Although

not yet reported, it may be possible to generate iPS cells by

transfection of primary NP cells with the Yamanaka factors.

This could allow for rapid expansion of a small number of

NP cells that would be sufficient for tissue engineering an

organ.

ConclusionsClearly, the development of regenerative medicine for disease treatment is still a long way off. The replacement orregeneration of diseased or damaged tissue with an intactfunctional tissue generated by the individual’s own cells willbe a remarkable feat, and iPS cells represent an exciting advance that moves us one step closer to its realization. Thepathologist may have an important role to play in this treatment by providing the appropriate tissue or cells to thetissue engineer.

AcknowledgementsThis research was supported by the Canadian Institutes ofHealth Research.

References1. Daar AS. Regenerative medicine: a taxonomy for addressing ethical, legal and

social issues. In: Gutmann T, Daar AS, Sells RA, Land W, eds. Ethical, Legal

and Social Issues in Organ Transplantation. Munich: PABST Publishers;

2005:368–77.

2. Greenwood HL, Thorsteinsdottir H, Perry G, et al. Regenerative medicine:

new opportunities for developing countries. Int J Biotechnol 2006;8:60–77.

3. Greenwood HL, Singer PA, Downey GP, et al. Regenerative medicine and the

developing world. PLoS Med 2006;3:e381.

4. Atala A. Engineering tissues, organs and cells. J Tissue Eng Regen Med

2007;1:83–96.

5. Sheikh H, Zakharian K, De La Torre RP, et al. In vivo intervertebral disc re

generation using stem cell-derived chondroprogenitors. J Neurosurg Spine

2009;10:265–72.

6. Allen MJ, Schoonmaker JE, Bauer TW, et al. Preclinical evaluation of a poly

(vinyl alcohol) hydrogel implant as a replacement for the nucleus pulposus.

Spine 2004;29:515–23.

7. Frymoyer JW. Magnitude of the problem. In: Wiesel SW, Weinstein JN,

Herkowitz HN, et al., eds. The Lumbar Spine. Philadelphia (PA):

W.B. Saunders; 1996:8–15.

8. Humzah MD, Soames RW. Human intervertebral disc: structure and function.

Anat Rec 1988;220:337–56.

9. Buckwalter JA. Aging and degeneration of the human intervertebral disc.

Spine 1995;20:1307–14.

10. Eyre DR, Muir H. Types I and I collagens in intervertebral disc. Interchanging

radial distributions in annulus fibrosus. Biochem J 1976;157:267–70.

11. Hutton WC, Ganey TM, Elmer WA, et al. Does long-term compressive loading

on the intervertebral disc cause degeneration? Spine 2000;25:2993–3004.

12. Sztrolovics R, Grover J, Cs-Szabo G, et al. The characterization of versican

and its message in human articular cartilage and intervertebral disc. J Orthop

Res 2002;20:257–66.

13. Trout JJ, Buckwalter JA, Moore KC, et al. Ultrastructure of the human inter

vertebral disc. I. Changes in notochordal cells with age. Tissue Cell

1982;14:359–69.

14. Maldonado BA, Oegema TRJ. Initial characterization of the metabolism of

intervertebral disc cells encapsulated in microspheres. J Orthop Res

1992;10:677–90.

15. Holm SH. Nutritional and pathophysiologic aspects of the lumbar

intervertebral disc. In: Wiesel SW, Weinstein JN, Herkowitz HN, et al., eds.

The Lumbar Spine. Philadelphia (PA): W.B. Saunders; 1996:285–310.

16. Garfin SR, Herkowitz HN. Lumbar disc degeneration: normal aging or a

disease process? In: Wiesel SW, Weinstein JN, Herkowitz HN, et al., eds. The

Lumbar Spine. Philadelphia (PA): W.B. Saunders; 1996:458–72.

17. Oegema TR. Biochemistry of the intervertebral disc. Clin Sports Med

1993;12:419–39.

18. Buckwalter JA, Mow VC, Boden SD, et al. Intervertebral disk aging,

degeneration, and hernation. In: Buckwalter JA, Einhorn TA, Simon SR, eds.

Orthopaedic Basic Science, 2nd edit ion. Rosemont (IL): American Academy

of Orthopaedic Surgeons; 2000:557–66.

19. Hanley EN Jr, Delamarter RB, McCullouch JA, et al. Surgical indications and

techniques. In: Wiesel SW, Weinstein JN, Herkowitz HN, et al., eds. The

Lumbar Spine. Philadelphia (PA): W.B. Saunders; 1996:492–524.



20. Siepe CJ, Mayer HM, Wiechert K, et al. Clinical results of total lumbar disc

replacement with ProDisc II: three-year results for different indications. Spine

2006;31:1923–32.

21. Levin DA, Hale JJ, Bendo JA. Adjacent segment degeneration following spinal

fusion for degenerative disc disease. Bull NYU Hosp Jt Dis 2007;65:29–36.

22. Hench L, Polak J. Third generation biomedical materials. Science

2002;295:1014–7.

23. Spaans CJ, Belgraver VW, Rienstra O, et al. Solvent-free fabrication of

micro-porous polyurethane amide and polyurethane-urea scaffolds for repair

and replacement of the knee-joint meniscus. Biomaterials 2000;21:2453–60.

24. Boccaccini AR, Roether JA, Hench LL, et al. A composites approach to tissue

engineering. Ceram Eng Sci Proc 2002;23:805–16.

25. Boyd LM, Carter AJ. Injectable biomaterials and vertebral endplate treatment

for repair and regeneration of the intervertebral disc. Eur Spine J

2006;15:S414–21.

26. Navarro M, Michiardi A, Castaño O, et al. Biomaterials in orthopaedics. J R

Soc Interface 2008;5:1137–58.

27. Halloran DO, Grad S, Stoddart M, et al. An injectable cross-linked scaffold

for nucleus pulposus regeneration. Biomaterials 2008;29:438–47.

28. Séguin CA, Grynpas MD, Pilliar RM, et al. Tissue engineered nucleus pulposus

tissue formed on a porous calcium polyphosphate substrate. Spine

2004;29:1299–306, discussion 1306–7.

29. Wang YH, Kuo TF, Wang JL. The implantation of non-cell-based materials to

prevent the recurrent disc herniation: an in vivo porcine model using

quantitative discomanometry examination. Eur Spine J 2007;16:1021–7.

30. Nagae M, Ikeda T, Mikami Y, et al. Intervertebral disc regeneration using

platelet-rich plasma and biodegradable gelatin hydrogel microspheres. Tissue

Eng 2007;13:147–58.

31. Maroudas A, Stockwell RA, Nachemson A, et al. Factors involved in the

nutrition of the human lumbar intervertebral disc: cellularity and diffusion

of glucose in vitro. J Anat 1975;20:113–30.

32. Gruber HE, Stasky AA, Hanley EN Jr. Characterization and phenotypic

stability of human disc cells in vitro. Matrix Biol 1997;16:285–8.

33. Horner HA, Roberts S, Bielby RC, et al. Cells from different regions of the

intervertebral disc: effect of culture system on matrix expression and cell

phenotype. Spine 2002;27:1018–28.

34. Le Maitre CL, Freemont AJ, Hoyland JA. Accelerated cellular senescence in

degenerate intervertebral discs: a possible role in the pathogenesis of inter

vertebral disc degeneration. Arthritis Res Ther 2007;9:R45.

35. Jim JJ, Noponen-Hietala N, Cheung KM, et al. The TRP2 allele of COL9A2 is

an age-dependent risk factor for the development and severity of

intervertebral disc degeneration. Spine 2005;30:2735–42.

36. Aladin DM, Cheung KM, Chan D, et al. Expression of the Trp2 allele of

COL9A2 is associated with alterations in the mechanical properties of human

intervertebral discs. Spine 2007;32:2820–6.

37. Muñoz M, Rodríguez A, De Frutos C, et al. Conventional pluripotency

markers are unspecific for bovine embryonic-derived cell-lines.

Theriogenology 2008;69:1159–64.

38. Swijnenburg R-J, Schrepfer S, Govaert JA, et al. Immunosuppressive therapy

mitigates immunological rejection of human embryonic stem cell xenografts.

Proc Natl Acad Sci U S A 2008;105:12991–6.

39. Richardson SM, Hoyland JA. Stem cell regeneration of degenerated

intervertebral discs: current status. Curr Pain Headache Rep 2008;12:83–8.

40. Nakahara M, Takagi M, Hattori T, et al. Effect of subcultivation of human

bone marrow mesenchymal stem on their capacities for chondrogenesis,

supporting hematopoiesis, and telomea length. Cytotechnology

2005;47:19–27.

41. Mendes SC, Tibbe JM, Veenhof K, et al. Bone tissue-engineered implants using

human bone marrow stromal cells. Tissue Eng 2002;8:911–20.

42. Le Maitre CL, Baird P, Freemont AJ, et al. An in vitro study investigating the

survival and phenotype of mesenchymal stem cells following injection into

nucleus pulposus tissue. Arthritis Res Ther 2009;11:R20.

43. Richardson SM, Hughes N, Hunt JA, et al. Human mesenchymal stem cell

differentiation to NP-like cells in chitosan-glycerophosphate hydrogels. Bio

materials 2008;29:85–93.

44. Sakai D, Mochida J, Yamamoto Y, et al. Transplantation of mesenchymal stem

cells embedded in atelocollagen gel to the intervertebral disc: a potential

therapeutic model for disc degeneration. Biomaterials 2003;24:3531–41.

45. Sakai D, Mochida J, Iwashina T, et al. Regenerative effects of transplanting

mesenchymal stem cells embedded in atelocollagen to the degenerated inter

vertebral disc. Biomaterials 2006;27:335–45.

46. Henriksson HB, Svanvik T, Jonsson M, et al. Transplantation of human mes

enchymal stems cells into intervertebral discs in a xenogeneic porcine model.

Spine 2009;34:141–8.

47. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse

embryonic and adult fibroblast cultures by defined factors. Cell 2006;

126:663–76.

48. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells

from adult human fibroblasts by defined factors. Cell 2007;131:861–72.

49. Liu X, Huang J, Chen T, et al. Yamanaka factors critically regulate the

developmental signaling network in mouse embryonic stem cells. Cell Res

2008;18:1177–89.

50. Woltjen K, Michael IP, Mohseni P. piggyBac transposition reprograms fibrob

lasts to induced pluripotent stem cells. Nature 2009;458:766–70.


ORIGINAL ARTICLE

Stanley Todd, MD, Mukund Tinguria, MD, P. Wentworth, MD, A. Croal, MD, Katherine Chorneyko, MD

ABSTRACTQuality assurance (QA) and quality improvement (QI) programs are mandatory components of virtually all

laboratory accreditation processes, with the ultimate purpose of decreasing laboratory errors and increasing

patient safety. QA/QI in anatomical pathology encompasses preanalytical, analytical, and postanalytical factors

in the areas of cytopathology, histopathology, immunohistochemistry, and surgical and autopsy pathology.

Unlike other areas of the laboratory where QA/QI may involve monitoring specific analytes and, in many

instances, may be automated, QA/QI in surgical pathology is labour intensive since the gold standard for a

“correct” diagnosis is peer review. Although the principles of all surgical pathology QA/QI programs are the

same, the application in individual laboratories depends on departmental demographics and other local factors.

This review summarizes 1 year (2008) of a surgical pathology QA/QI program in a community hospital setting

and addresses some of the challenges in maintaining an active and effective QA/QI program.

RÉSUMÉPour être agréé, le laboratoire doit se doter de programmes d’assurance de la qualité et d’amélioration de la

qualité, dans le but ultime de réduire au minimum les erreurs et de veiller à la sécurité du patient. L’assurance

et l’amélioration de la qualité en anatomie pathologique englobent les phases préliminaire, analytique et

subséquente de la cytopathologie, de l’histopathologie, de l’immunohistochimie, ainsi que la pathologie

chirurgicale et l’autopsie. Là où l’assurance et l’amélioration de la qualité dans d’autres disciplines de laboratoire

passent par la surveillance de substances à analyser précises et peuvent être automatisées, ces processus en

pathologie chirurgicale sont exigeants en main-d’œuvre étant donné que la vérification de référence du

diagnostic « juste » consiste en l’examen par des pairs. Bien que les principes de l’assurance et de l’amélioration

de la qualité en pathologie chirurgicale soient les mêmes dans tous les programmes, la mise en application du

programme au laboratoire varie selon les caractéristiques démographiques et d’autres facteurs propres à

l’établissement. L’article de fond résume une année (2008) du programme d’assurance et d’amélioration de la

qualité en pathologie chirurgicale d’un hôpital communautaire et aborde certains des défis que pose le

programme efficace.

Surgical Pathology Quality Assurance/QualityImprovement in a Community Hospital:

A Year in Review

Stanley Todd, MD, Mukund Tinguria, MD, P. Wentworth, MD, A. Croal, MD, Katherine Chorneyko, MD, are with the BrantCommunity Healthcare System, Brantford General Hospital, Brantford, Ontario. Katherine Chorneyko can be contacted [email protected] article was peer reviewed.

Quality assurance (QA) and quality improvement (QI)

initiatives are mandatory components of virtually all

laboratory accreditation processes. Furthermore, most

laboratories recognize that an organized and active QA/QI

program enhances patient safety and minimizes error. There

are guidelines and recommendations as to how anatomical

pathology QA and QI programs should be structured1–3;

however, within these frameworks there is room for

flexibility since there is variability in the types of clinical

services individual anatomical pathology laboratories


support, as well as differences in local resources. The

analytical aspect of an anatomical pathology QA program

encompasses many components including histology,

histochemistry, immunohistochemistry, intraoperative

consultation, and the final diagnosis or interpretation. The

gold standard for “correctness” in diagnostic interpretation

is generally considered to be peer review, and many different

types of review can and do take place: intradepartmental

consultation, external consultation, cancer centre reviews,

and the College of Physicians and Surgeons of Ontario Peer

Assessment Programme.1,4 These activities can be

monitored in diverse and innovative ways, and the sharing

of how different QA/QI programs are structured is one way

to communicate ideas that may be of interest to the

anatomical pathology community at large.

The purpose of this review is to provide one example of a

surgical pathology QA/QI program in an Ontario

community hospital, with a discussion of the challenges

faced in implementing such a program.

Description of a QA Program in Anatomical PathologyThe Brant Community Healthcare System (BCHS) consists

of two sites: the Brantford General Hospital, an acute care

facility with 300-plus beds, and Willet Hospital, which

provides predominantly outpatient services. The Brantford

General Hospital is the regional centre for pediatrics,

obstetrics, gynecology, critical care, emergency care, and

surgery services. In total, BCHS provides health care services

for a population of approximately 120,000 people.

The Anatomical Pathology Department, located at the

Brantford General Hospital, handles approximately 8,700

surgical specimens, 2,300 gynecological/nongynecological

cytology specimens, and 180 bone marrow aspirates and

biopsies per year. This workload is handled by 3.0 full-time

equivalent (FTE) pathologists with a support staff of a

technical specialist (1.0 FTE), histotechnologists (2.5 FTE),

a pathology assistant (1.0 FTE), medical laboratory

assistants (1.8 FTE), a cytotechnologist (0.5 FTE), and an

administrative assistant. QA/QI monitoring of the technical

aspects of histopathology, immunohistochemistry, and

hematology are in place as well as interpretative and

technical aspects of cytology, but these are not considered

in this review.

The surgical pathology QA program was developed in 1997

and involves monthly review of QA benchmarks. One

pathologist is the designated QA coordinator, and one clerk

is assigned to assist in the administrative aspects of the

program. On a monthly basis, they collate statistics using a

combination of the hospital laboratory information system

(Meditech Client Server) and manual data entry on the

following indicators:

• Incomplete requisitions (excluding those that lack

a clinical history)

• Specimens inadequate for diagnosis

• Intraoperative consultations (agreement with

permanent, disagreement with permanent, deferred

cases)

• Internal consultations

• External consultations (including cancer centre reviews

and cases sent for second opinion)

• Peer-reviewed cases

• Corrected or revised reports (apart from those resulting

from cancer centre reviews or second opinions)

• Supplementary reports (e.g., ER/PR results, findings

following decalcification, additional information from

histochemistry/immunohistochemistry or

consultation)

In addition, a retrospective, monthly peer review of approx-

imately 25 cases is done. This review is semitargeted in the

sense that cases with a low likelihood of error such as hernia

sacs or vas deferens are not reviewed. Cases that have already

been subject to an internal or external consultation are also

not selected. An administrative assistant, who has been in-

structed as to which cases are appropriate for review, selects

the cases and organizes the paperwork and slides. The

pathologists review the cases under the following criteria:

• Adequacy of clinical history

• Gross description

• Microscopic description

• Ancillary studies

• Diagnosis

• Turnaround time

SURGICAL PATHOLOGY QUALITY ASSURANCE/QUALITYIMPROVEMENT IN A COMMUNITY HOSPITAL


Discrepant diagnoses are qualified as to minor (no impact

on patient care or management) or major (with impact on

patient care or management, or a significant change in

diagnosis even with no clinical impact). All discrepancies are

discussed with the original pathologist, and a decision is

made regarding the appropriate course of action. In some

instances, an additional external consultation may be

undertaken. If necessary, the clinician is contacted directly

and a corrected report is issued.

On a monthly basis, the QA statistics are presented to the

hospital Medical Quality Improvement Committee. This

committee considers all aspects of quality of care in the

hospital and has representation from all departments as well

as the Risk and Quality Management Department. All

discrepant diagnoses identified either by peer review or

external review are disclosed, with the course of action.

Incident reports, which are generated for errors arising from

nonprofessional actions (e.g., specimen mislabeling), are

tracked in a hospital-wide electronic patient safety system

(Risk Monitor Pro Safety Reporting System) and are

monitored by risk management, which reports to the

Medical Quality Improvement Committee.

Summary of 2008 StatisticsIn 2008, three full-time pathologists handled the following

workload: 8,652 surgical pathology cases, 180 bone marrow

aspirates and biopsies, 58 peripheral smear interpretations,

1,221 gynecological cytology cases, 1,142 non-gynecological

cytology cases, 90 semen analyses, and 78 autopsies.

With regard to tracking of incomplete requisitions and

inadequate specimens, a total of 649 of 8,652 cases had

incomplete requisitions (7.5%). These represent specimens

that could not be accessioned at the time of specimen receipt

due to incomplete patient or specimen data (not including

incomplete clinical history). Monthly tracking of incomplete

requisitions shows that there is monthly variability ranging

from 4 to 11% (Table 1). Specimens were considered inad-

equate for diagnosis if there was insufficient cellular material

or another reason for which a specimen could not be inter-

preted, for example, extensive cautery artifact. Overall, in

2008 less than 1% (monthly range 0.3–1.4%) of the speci-

mens fell into this category.

Table 1. Incomplete Requisitions and Inadequate Specimens, Brant Community Healthcare System, 2008

No. of No. of

No. of Incomplete Cases Inadequate

Month Surgical Cases Requisitions (%) for Diagnosis (%)

January 709 57 (7) 4 (0.6)

February 720 74 (10) 4 (0.6)

March 552 37 (7) 3 (0.5)

April 852 54 (6) 5 (0.6)

May 742 26 (4) 3 (0.4)

June 789 73 (9) 7 (0.9)

July 772 87 (11) 7 (0.9)

August 538 49 (9) 4 (0.7)

September 764 65 (9) 6 (0.8)

October 846 56 (7) 12 (1.4)

November 727 41 (6) 2 (0.3)

December 641 30 (5) 5 (0.8)

Intraoperative consultation was requested in 18 cases, and

in 15 there was agreement with the final surgical diagnosis

(83%). In two cases the diagnosis was deferred, and in one

case there was a disagreement with the final surgical

diagnosis due to sampling (an ovarian cyst diagnosed as

benign mucinous cystadenoma on frozen section and

borderline mucinous tumour on permanent sections).

In 2008, a total of 12.7% of cases were seen by two or more

pathologists (internal consultations, external consultations,

and peer review). Internal consultations were more

numerous than external consultations, except in the summer

month of July (Figure 1). In 2008, 7% of cases were reviewed

as internal consultations, while 4% were reviewed as external

consultations or were subject to external review (cancer

centre or other requested reviews). In total, there were 300

(3.5%) semitargeted peer-reviewed cases, 595 (6.9%)

internal consultations, and 311 (3.6%) external

consultations. In some instances, internal consultations were

also referred for external review. Peer review detected nine

discrepancies (four minor and five major), representing

0.1% of the 2008 cases. Cases sent for external consultation

are considered preliminary or deferred diagnoses until the

second opinion has been received and, as such, are not

TODD ET AL.


considered discrepant. Discrepancies from cancer centre

reviews were also monitored and documented. No major or

minor discrepancies were identified in these latter reviews.

For any significant discrepancies, clinicians are contacted

and corrected reports are issued. Reports corrected for other

reasons (not part of the external or peer-review process) are

monitored; in 2008, five corrected or revised reports were

issued in this category. Supplementary reports, in which

additional information from ancillary tests, external

consultations, or decalcification was provided, were issued

in 196 cases (2.3%).

Figure 1. Internal and external consultations, Brant Com-munity Healthcare System, 2008.

DiscussionIn the wake of three major public inquires into errors in

anatomical pathology,5–7 as well as the current atmosphere

of increasing case complexity, it is important for an

anatomical pathology service to have a robust QA/QI

program. However, a comprehensive and effective program

becomes more difficult to administer as workload

complexity increases and budget constraints continue. The

program at BCHS is one example of a community health

care QA/QI program that monitors specific preanalytical,

analytical, and postanalytical factors on a monthly basis.

Although specific aspects of QA programs have been

published in the literature – for example, specimen labelling

errors,8 frozen section/permanent section monitoring,9 and

second reviews10 – there are very few publications outlining

the components of a QA/QI program in an individual

hospital. In 1998, a 5-year review of the internal QA

program in a tertiary care teaching hospital in Australia was

summarized11; however, to our knowledge, there is no

published review of a community hospital QA/QI program.

Regular monitoring of indicators can reaffirm that an

anatomical pathology service is functioning well and, in

addition, can identify specific targets for possible

intervention or education. For example,

incomplete requisitions are a problem as they

require laboratory staff to spend time sorting

out the deficiencies. This causes delays in

accessioning of cases and diverts laboratory staff

from other duties. The monitoring of

incomplete requisitions as part of the BCHS

QA/QI program identified continued

deficiencies in this area, and it was targeted as

an area for improvement. This has been

followed up by the organization of short, in-

service education sessions about this topic to

clinical areas in which specimens are procured.

Continued monitoring of incomplete

requisitions will show if this intervention has

been successful.

The success of any QA program is measured by

improved patient safety through a decreased error rate. A

review of the QA program at BCHS shows that although

errors are very low (<1%), they can occur. One challenge

faced by this department is to ensure timely identification

and correction of errors. The peer-review process occurs 1

month following sign out; while this is within a reasonable

time frame, ideally it should be shortened. Prospective peer

review would be preferable since errors would be corrected

before the release of a case; however, workload and staffing

resources limit the ability to provide this type of QA/QI. It

should be noted that, as in most departments, many cases

are shown to other pathologists as internal departmental

consultations, which is a form of prospective peer review.

Nonetheless, it is hoped that with continued discussion of

resources, a prospective QA process can be implemented.

As health care becomes more complex and fiscal constraints

0

20

40

60

80

100

120

140

Janu

ary

Februa

ryMarc

hApri

lMay

June Ju

ly

Augus

t

Septem

ber

Octobe

r

Novem

ber

Decem

ber

Num

ber o

f cas

es

Seen by 2 or more pathologistsInternal consultationsExternal consultations

SURGICAL PATHOLOGY QUALITY ASSURANCE/QUALITYIMPROVEMENT IN A COMMUNITY HOSPITAL


continue, the main challenge in realizing an effective QA/QI

program is resources. Although in BCHS there is

administrative and technical support, as service workload

increases it is more difficult for support staff to find time to

gather paperwork, collate statistics, and pull slides. For the

pathologists, increasing work volumes and complexity

coupled with other service duties as well as multidisciplinary

round preparation, committee work, other QA activities,

and continuing medical education requirements make it

challenging to complete the peer-review process in a timely

fashion. Furthermore, when the review is semitargeted so

that complex and critical cases are largely assessed, more

time is required than if only simple cases were targeted.

Therefore, in any consideration of departmental workload,

not only the number of QA cases reviewed but also their

complexity must be taken into account.

Unlike larger community hospitals or academic

departments, a medical staff of only three pathologists faces

the challenge of a limited pool of individuals for peer review.

Across Canada, there are smaller, and occasionally solo,

pathology practices, which would make implementation of

a QA/QI even more challenging. There may be opportunities

for larger centres to provide support for smaller ones as long

as there are adequate resources to do so. Virtual microscopy

will likely be important in future QA/QI initiatives of this

sort.12–14

ConclusionA QA/QI program in anatomical pathology is an organized,

dynamic ongoing activity that enhances patient safety and

minimizes error. Although other laboratories in Canada will

have similar but individual QA/QI programs, they all may

face the same challenges in regard to resources and

implementation. Increased attention to resources for

anatomical pathology QA/QI initiatives is imperative to

maintain the high quality of anatomical pathology services

in Canada.

AcknowledgementsThe authors gratefully acknowledge the contributions of

Dorothy McLean and the histology laboratory staff, who

provide administrative support and without whom the

program could not exist.

References1. Association of Directors of Anatomic and Surgical Pathology.

Recommendations for quality assurance and improvement in surgical and

autopsy pathology. Hum Pathol 2006;37:985–8.

2. Quality improvement plan components and monitors. In: Nakhleh RE,

Fitzgibbons PL, eds. Quality Management in Anatomical Pathology.

Northfield (IL): College of American Pathologists; 2005:45–76.

3. Ontario Quality Management Programme – Laboratory Services and Ontario

Laboratory Accreditation. Ontario Laboratory Accreditation and Guidance

Information, Version 4.1. Toronto (ON): Ontario Quality Management

Programme – Laboratory Services and Ontario Laboratory Accreditation; 2008.

4. College of Physicians and Surgeons of Ontario. Peer assessment. Toronto (ON):

The College; www.cpso.on.ca/members/peerassessment.

Accessed September 21, 2009.

5. Goudge ST. Inquiry into pediatric forensic pathology in Ontario.

Toronto (ON): Ministry of the Attorney General, 2008; www.goudgeinquiry.ca.

Accessed May 20, 2009.

6. Cameron MA. Commission of inquiry on hormone receptor testing. St. John’s

(NL): Department of Justice, 2009; www.cihrt.nl.ca. Accessed May 20, 2009.

7. Creaghan PS. Commission of inquiry into pathology services at the Miramichi

Regional Health Authority. Miramichi (NB): The Commission, 2008;

www.miramichicommission.ca. Accessed May 20, 2009.

8. Wagar EA, Stankovic AK, Raab SS, et al. Specimen labeling errors: a Q probe

analysis of 147 laboratories. Arch Pathol Lab Med 2008;132:1617–22.

9. Raab SS, Tworak JA, Souers R et al. The value of monitoring frozen section-

permanent section correlation data over time. Arch Pathol Lab Med

2006;130:337–42.

10. Safrin RE, Bark CJ. Surgical pathology signout: routine review of every case by

a second pathologist. Am J Surg Pathol 1993;17:1190–2.

11. Zardawi IM, Bennett G, Jain S, et al. Internal quality assurance activities of a

surgical pathology department in an Australian teaching hospital. J Clin Pathol

1998;51:695–9.

12. Evans AJ, Henry PC, Van der Kwast TH, et al. Interobserver variability between

expert urological pathologists for extraprostatic extension and surgical margin

status in radical prostatectomy specimens. Am J Surg Pathol 2008;32:1503–12.

13. Fine JL, Grzybicki DM, SIlowash R, et al. Evaluation of whole slide image

immuno histochemistry interpretation in challenging prostate needle biopsies.

Hum Pathol 2008;39:564–72.

14. Graham AG, Bhattacharyya AK, Scott KM, et al. Virtual slide telepathology for

an academic teaching hospital surgical pathology quality assurance program.

Hum Pathol 2009;40:1129–36.

TODD ET AL.

ORIGINAL ARTICLE

Manon Auger, MD, FRCP(C)

ABSTRACTThe National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference provides a

framework of guidelines on the indications, pre-fine-needle aspiration requirements, training, techniques,

diagnostic terminology, use of ancillary studies, and post-fine-needle aspiration testing and treatment options

for thyroid fine-needle aspirates. This article is a synopsis of those guidelines, presented as the Kulcsar Lecture

for the Canadian Society of Cytology symposium at the annual meeting of the Canadian Association of

Pathologists in 2009.

RÉSUMÉLa Conférence sur l’état de la science quant à la biopsie de la thyroïde par aspiration à l’aiguille du National

Cancer Institute a donné lieu à l’élaboration d’un cadre de référence de lignes directrices sur les indications,

les critères préalables, la formation, les techniques, la terminologie diagnostique, les études connexes, les

épreuves subséquentes et les options thérapeutiques selon la nature de l’aspirat. L’article, qui expose l’essentiel

de ces lignes directrices, reprend la conférence Kulcsar présentée au symposium de la Société canadienne de

cytologie lors du congrès annuel de l’Association canadienne des pathologistes en 2009.

Kulcsar Lecture 2009: Highlights from the National Cancer Institute

Thyroid Fine Needle Aspiration State of the Science Conference

Manon Auger, MD, FRCP(C), is a member of the Department of Pathology, McGill University Health Center and McGill Uni-versity, Montreal, Quebec. Manon Auger is the editor of the cytopathology section of the Canadian Journal of Pathology.She can be contacted at [email protected] article was peer reviewed.

It is an honour for me to present the Kulcsar Lecture,which was instituted in 1990 and has since been given

annually to the Canadian Society of Cytology (CSC) in

memory of Dr. David D. Kulcsar. Dr. Kulcsar played a

primordial role in the development of the CSC as one of the

founding members of the Canadian Cytology Council

(CCC), later renamed CSC. He was the first secretary-

treasurer of the CCC/CSC from 1961 to 1966 and the editor

of the CCC newsletter; he became chair of the CSC in 1967–

1968. Interestingly, Dr. Kulcsar, along with Drs. Donald W.

Thompson and George H. Anderson, was involved in an

early survey of cytopathology laboratories across Canada in

1967.1 The only nongynecological specimens specifically

mentioned in their report were pulmonary, gastric, urinary,

and serous effusions; all the others were are grouped under

the “miscellaneous” category, presumably including a small

number of thyroid fine-needle aspirations (FNAs). This

underscores the evolution in the practice of cytopathology

over the past 40 years, with thyroid FNAs now representing

one of the most common nongynecological specimens

encountered in many cytopathology laboratories. This

change stems from a combination of factors, including the

fact that thyroid nodules are very common and are found

in approximately 4–7% of the adult population. Because

most are benign, surgery for all thyroid nodules is not

appropriate, and FNA is now recognized as the most

accurate and cost-effective method for evaluating thyroid

nodules.2

One problematic aspect of thyroid FNAs is that pathologists

differ widely in how they report them. This proliferation of


reporting formats has made it difficult to compare data for

parameters such as sensitivity, specificity, and positive and

negative predictive values between centres, and is confusing

for clinicians to interpret reports. This variability is best

documented in Helen Wang’s review3 of the published

-literature (87 publications between 1966 and December

2004) on thyroid FNA reporting: she documents at least 17

different schemes for reporting thyroid FNA results, ranging

from simplistic two-category schemes (i.e., benign versus

suspicious/malignant, corresponding to the clinically

relevant decision making of surgical versus nonsurgical

follow-up) to six or more schemes containing one or more

layers of uncertainty between benign and malignant.

Although there have been attempts at standardization of

thyroid FNA reporting over the years, by the Papanicolaou

Society of Cytopathology Task Force4 and the American

Association of Clinical Endocrinologists5 among others,

none has been widely accepted.

In light of the above, the National Cancer Institute (NCI),

under the initiative of Dr. Andrea Abati, sponsored the

Thyroid FNA: State of the Science Conference, which was

held on October 22–23, 2007, in Bethesda, Maryland. The

conference was prefaced by an online web-based bulletin

board discussion between May 1 and August 15, 2007. Six

committees were appointed, consisting of recognized

experts in the field of thyroid, including cytopathologists,

surgical pathologists, endocrinologists, surgeons, and

radiologists. The goal of the conference was to encourage

interdisciplinary dialogue and education regarding the

evaluation, management, and interpretative reporting of

thyroid nodules. The discussions at the 2-day “live”

conference were efficiently and tactfully co-moderated by

Drs. Edmund S. Cibas, a cytopathologist, and Susan J.

Mandel, an endocrinologist, both well respected in the field

of thyroid diseases.

This synopsis addresses only selected highlights from the

NCI conference; detailed reviews on this topic are

available.6–16 At the time of this writing, a comprehensive

atlas edited by Drs. Edmund Cibas and Syed Ali, related to

each of the diagnostic categories endorsed at the NCI

conference, was to be published in the fall of 2009, followed

by an online atlas.

Indications for Thyroid FNA and Pre-FNA RequirementsThe indications for performing an FNA of a thyroid nodule

depend on the diagnostic modality used to discover the

nodule, that is, palpation versus imaging. With the increased

use of imaging, thyroid nodules are now more frequently

incidental findings during workup for other medical

problems, as opposed to usually discovered by palpation a

few years ago.

Nodules Discovered by PalpationBecause most nodules discovered by palpation measure

≥1 cm, they are considered clinically significant and deserving of further evaluation. A clinical history, physical

examination, especially of the thyroid and neck

lymph nodes, and thyroid-stimulating hormone (TSH)

measurements should be performed. If the TSH is normal

or high, then dedicated thyroid ultrasound (US) imaging

should be performed. If the TSH is suppressed

(<0.1 mIU/L), a radionuclide thyroid scan should be

performed. If the latter reveals a functioning nodule, an FNA

is not required because the risk of malignancy is very low; if

the nodule is isofunctional or hypofunctional, further

assessment by a dedicated thyroid ultrasonography is

warranted to determine the need for an FNA.

Nodules Discovered by ImagingNodules discovered by imaging may require FNA depending

on their size and on the type of imaging technique

performed. If the uptake within the thyroid on a positron

emission tomography (PET) scan is focal (rather than

diffuse), an FNA is indicated as these nodules have a

relatively high rate of malignancy (14–50%).17,18 In contrast,

if the uptake is diffuse, an FNA is not needed unless thyroid

ultrasonography shows a discrete nodule. Similarly, a “hot”

thyroid nodule on a sestamibi scan that is confirmed by

ultrasonography to be a discrete nodule should be aspirated

because the risk of malignancy ranges between 22 and

66%.19 If discovered by computed tomography (CT) or

magnetic resonance imaging (MRI), FNA is only required if

a dedicated thyroid ultrasonography shows suspicious

features. For nodules discovered by ultrasonography in

the general head and neck area, a dedicated thyroid

ultrasonography is recommended.

AUGER


KULCSAR LECTURE 2009

In general, nodules with a maximal diameter >1–1.5 cm

should undergo FNA unless they are a simple cyst or a

septate cyst without a solid component; alternatively, they

can be followed up at 6- to 18-month intervals if there are

no suspicious features by ultrasonography. If the nodules are

<1 cm diameter, an FNA should be considered if suspicious

ultrasonographic features are present, although a consensus

is lacking on how to deal with these.

What are the ultrasonographic features considered

suspicious in thyroid lesions? They include irregular or

lobulated margins, microcalcifications, hypoechoic solid

nodules, intranodular vascularity, a taller-than-wide shape,

signs of spread beyond the capsule of the nodule, and nodal

metastases.

US- versus Palpation-Guided FNAWhen should a thyroid FNA be performed by

ultrasonography versus palpation? In many cases, either

approach is acceptable. Because recent guidelines from the

American Thyroid Association recommend that all patients

with palpable nodules undergo a dedicated thyroid US

examination, an increasing number of FNAs are being done

by US guidance. Ultrasonography provides precise

information regarding the location, size, and structure

(cystic versus solid) of the lesion. In addition, published data

indicate that US guidance reduces the rate of nondiagnostic

and of false-negative specimens. Nevertheless, palpation-

guided FNA is still worthwhile. It has been performed with

a high rate of success over the years, is less costly, and is more

convenient. It is the preferred method where health care

resources are limited.

The circumstances when an US-guided FNA would be

preferred, if available, include (1) a diffusely enlarged

thyroid with no discrete nodule on physical examination,

(2) a poorly palpable nodule, (3) a predominantly cystic

nodule (>25%), (4) a small nodule (<1 cm), and (5) a prior

nondiagnostic FNA.

Pre-FNA RequirementsThe pre-FNA requirements relate to the informed consent

and the requisition form accompanying the thyroid FNA

specimen. The informed consent must include the

following: a description of procedure, a listing of potential

risks and complications, a mention of the possibility of

nondiagnostic results and of the potential need for re-

biopsy, and the patient’s identifying information (name and

address of person requesting test, name or unique identifier,

gender, age or birth date, name of test to be performed,

specimen source, and date of specimen collection). The

minimal clinical information required on the requisition for

thyroid FNA should include the following: (1) the exact

location of the nodule (allowing correlation with the

ultrasonographic findings); (2) the size of the nodule

(greatest dimension); (3) a history of hypothyroidism or

autoimmune thyroiditis, a positive antithyroid antibody test,

Graves’ disease, or iodine 131 (I131) or external beam

radiation therapy; and (4) a personal history of cancer

(including cancer of other body sites) and family history of

thyroid cancer. All these factors can influence the

interpretation of a thyroid FNA because they suggest

situations that change the expectations for a specific

morphological pattern or for the probability of cancer. For

example, while low serum TSH levels are associated with a

lower risk of thyroid carcinoma, cellular changes associated

with I131 therapy, external beam radiation, a prior FNA,

autoimmune thyroiditis, and Graves’ disease are all known

causes of false-positive diagnoses.

Thyroid FNA TrainingTraining for the performance of thyroid FNA is critical

because the majority of diagnostic failures are due to

nondiagnostic samples or to pathologists issuing diagnoses

on samples with inadequate material.20 Suggested

components of an FNA training program include, but are

not restricted to, studying an illustrated text or other

teaching aid on the technique, viewing a detailed

instructional video (such as those by Dr. Britt-Marie Ljung,

available on www.papsociety.org/fna/html, performing

bench practice (e.g., on bovine liver, or even on tomatoes

and oranges!), and, finally, performing actual sampling of

thyroid nodules under supervision. No specific number of

FNAs is stipulated to reach proficiency.

Thyroid FNA TechniquesThyroid FNAs are best performed using 25- or 27-gauge

needles to minimize bleeding and pain; 22- or 23-gauge


needles should be reserved for only drainage of the contents

of viscous colloid cysts. The technique can be successfully

performed using a needle alone, or with a syringe, with or

without a pencil- or pistol-type syringe holder, depending

on the preference of the aspirator. Local anesthesia usually

is not needed unless the patient is particularly anxious.

Thyroid FNA material for routine examination is best

handled by making direct smears on glass slides; these can

be air-dried for Romanovsky’s stain and/or spray-fixed or

wet-fixed in 95% alcohol for Papanicolaou’s stain. Other

preparatory options include cytospins, liquid-based

cytology, and cell blocks for tissue fragments as needed. If

resources permit, immediate on-site evaluation is helpful for

the assessment of specimen adequacy and for triaging

specimens for ancillary studies. If immediate assessment is

available, the sampling can stop when (1) a cyst is completely

drained and there is no residual mass, (2) a specific

malignancy is identified, or (3) the aspirate appears

adequate. Conversely, sampling should continue when (1) a

residual mass remains after a cyst is completely drained,

(2) the cellularity of the initial passes is inadequate, or

(3) the enrichment of a sample for a cell block or ancillary

studies is needed. If no on-site assessment is available, a

reasonable number of passes (two to five) from different

sites is recommended, with representative tissue from each

pass smeared on a slide and the remaining tissue rinsed into

a collection tube with transport fluid.

Of note, core biopsy of thyroid has failed to gain widespread

acceptance because of its small but definite risk of

complications (e.g., bleeding, nerve injury, tracheal

perforation, and tumour transplantation) compared with

FNAs. In addition, the differential diagnosis of benign versus

malignant follicular lesions is usually impossible on core

biopsies, and, most importantly, the nuclear features of

papillary carcinoma are more difficult to appreciate than in

FNAs. Therefore, FNA remains the best technique for the

initial investigation of thyroid nodules.

Diagnostic Terminology and Morphological CriteriaThe NCI diagnostic classification of thyroid lesions in FNA

specimens includes six categories: benign, follicular

neoplasm (specify if Hürthle cell neoplasm), atypia of

undetermined significance, suspicious, malignant, and

nondiagnostic. This classification is based on a risk of

malignancy for each category (Table 1).

Diagnostic Categories Alternate Acceptable Terminology Risk of Malignancy (%)

Benign 0–3

Atypia of undetermined significance Atypical follicular lesions 5–15

Cellular follicular lesions

Indeterminate follicular lesions

R/O neoplasm

Follicular neoplasm (specify if Hürthle) Suspicious for neoplasm 15–30

Suspicious for malignancy 60–75

Malignant 97–99

Nondiagnostic Unsatisfactory

FNA = fine-needle aspiration; R/O = rule out.

AUGER


Table 1. Categories of the National Cancer Institute Diagnostic Classification of Thyroid Lesions in FNA Specimens

Adequacy, Colloid Nodules, and CystsThe first decision to be taken before evaluating a thyroid

FNA is to decide if it is adequate or not. This topic is

controversial, and opinions have differed over the years. NCI

recommends that all thyroid FNAs must be technically

adequate, with well-preserved and well-prepared thyroid

follicular epithelial cells for interpretation; at least six

clusters of at least 10 follicular cells must be present to

ensure adequacy. The term nondiagnostic (synonyms:

unsatisfactory, inadequate, and insufficient) should be

reserved for specimens of limited cellularity, containing no

follicular epithelium, or of poor preservation precluding

cellular evaluation.

Exceptions to the adequacy requirements can be made in the

following circumstances: (1) any specimen with any atypical

features cannot be called nondiagnostic or unsatisfactory

and should be placed in the “atypical” category; (2) cases of

lymphocytic thyroiditis, because they may occasionally yield

only lymphocytes with few follicular cells; and (3) FNAs

containing abundant thick colloid (i.e., slide full of colloid)

and little else. This latter exception was one of the “hot

topics” at the NCI conference and generated a long

discussion with many different views expressed. In the end,

it was decided that because an FNA containing abundant

colloid and little else most likely represents a colloid nodule

and carries an insignificant risk of malignancy, it can be

included in the benign category as being “suggestive of

colloid nodule.”

Another hot topic at the NCI conference was the question

of how to categorize FNAs containing only (or mostly)

macrophages; that is, whether to place them in the benign

versus the nondiagnostic versus their own category. Simple,

noncomplex cysts carry a risk of malignancy of 1–4%,

whereas mixed (solid and cystic nodules), large (>3 cm), and

recurring cysts carry a risk of malignancy of up to 14%.

Therefore, in view of the fact that a small but significant

percentage of cystic specimens may represent sampling from

a cystic papillary thyroid carcinoma (PTC), it was decided

that reassurance with a “benign” category would be

inappropriate. The conclusion was that cystic specimens

containing macrophages only (or macrophages with less

than six groups of follicular cells) should be diagnosed as

nondiagnostic/insufficient for diagnosis: cyst fluid only with a

recommendation that correlation should be made with the

ultrasonographic findings; an optional disclaimer that

“cystic PTC cannot be excluded” may be added (Figure 1).

A detailed description of the morphological criteria of each

diagnostic category is beyond the scope of this synopsis; only

selected topics are covered.

Figure 1. Thyroid fine-needle aspiration of a cyst showingmacrophages only. Such specimens, as well as those containing less than six groups of 10 follicular cells in addition to the foamy or hemosiderin-ladenmacrophages, should be diagnosed as nondiagnostic:cyst contents only, rather than benign to minimize false-negative results. (Papanicolaou’s stain, original magnification 200x)

BenignThe general category benign consists mostly of nodular

goitre, hyperplastic/adenomatoid nodule, colloid nodule,

chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis),

and granulomatous thyroiditis. The benign category carries

a very low risk of malignancy. In general, the non-thyroiditis

lesions are characterized by a predominantly honeycomb or

macrofollicular arrangement of follicular cells (a circular

formation composed of >15 follicular cells that are evenly

spaced) (Figure 2).



Figure 2. Thyroid fine-needle aspiration of nodular goitre.The macrofollicular configuration of the follicular cells canalso produce a honeycomb arrangement upon flatteningof the follicular spheres when spread on to a slide. Thispattern usually connotes a non-neoplastic/benignprocess. The histological follow-up in this case wasnodular hyperplasia/nodular goitre. (Papanicolaou’sstain, original magnification 100x)

Follicular Neoplasms(Specify if Hürthle Cell Neoplasms)The diagnostic category follicular neoplasm applies to non-

papillary follicular-patterned neoplasms, including Hürthle

cell neoplasms. This category carries an intermediate risk of

malignancy. Many terms have been used in the past

for follicular neoplasms, including microfollicular

proliferation/lesion, suggestive of neoplasm, follicular lesion,

and suspicious for follicular neoplasm; of those, only the latter

term is still acceptable as alternate wording in lieu of

follicular neoplasm.

In general, specimens falling into this category should be

hypercellular and characterized by follicular cells arranged

in a predominantly syncytial or microfollicular pattern (a

circular formation composed of six to 15 follicular cells)

and/or trabeculae (cords), with scant colloid (Figure 3). The

nuclear features of PTC should be absent. The distinction

between follicular adenoma and follicular carcinoma cannot

be made on cytology.

Figure 3. Thyroid fine-needle aspiration of follicular adenoma with a microfollicular arrangement of the cells.This architecture usually indicates a neoplastic (benignor malignant) process. The histological follow-up revealeda follicular adenoma. (Papanicolaou’s stain, original magnification 200x)

Hürthle cell neoplasms are also characterized by

hypercellularity and a predominant syncytial, microfollicular

pattern and/or trabeculae (cords) (of Hürthle cells) with

scant colloid. In contrast to most follicular neoplasms,

Hürthle cell neoplasms tend to exhibit more single/

dyscohesive cells. There is usually a pure population of

Hürthle cells, and these typically exhibit prominent nucleoli,

whereas Hürthle cells in non-neoplastic lesions usually have

inconspicuous or absent nucleoli. As is the case for follicular

neoplasms, the distinction between Hürthle cell adenoma

and Hürthle cell carcinoma cannot be made on cytology.

Atypia of Undetermined SignificanceThe term atypia of undetermined significance (AUS)

represents a heterogeneous category of cases and should be

reserved for cases exhibiting cytological findings that are not

convincingly benign, yet the degree of cellular or

architectural atypia is not sufficient for an interpretation

of follicular/Hürthle cell neoplasm or suspicious for

AUGER


malignancy. This category should represent <7% of all

thyroid FNAs, and the risk of malignancy should be in the

range of 5–15%.

Some cases fall into the AUS category because they

correspond to compromised specimens due to low

cellularity, poor fixation, or obscuring blood. Other types of

cases falling into this category include the following:

• Atypical follicular lesion of undetermined significance

(FLUS) – that is, follicular lesions between benign and

follicular neoplasms, for example, with mixed micro-

and macrofollicular patterns but without predominance

of either

• Atypical Hürthle cell lesion of undetermined

significance (HUS) – Hürthle cell lesions between

benign and Hürthle cell neoplasms, for example,

monotonous Hürthle cell population but without other

features of Hürthle cell neoplasm

• Atypical cells present, cannot rule out PTC – some

concern about PTC but insufficient to be diagnosed as

“suspicious”

• Other nonspecific changes that cause concern; these

should be specified in the diagnosis, for example,

atypical cyst-lining cells

In summary, cases falling into the AUS category do so based

on architectural atypia, cytological atypia, or a compromised

specimen. As with atypical squamous cells in gynecological

cytology when this term was first introduced into the

diagnostic scheme, the new category AUS will require more

rigorously defined morphological criteria. The publication

of the atlas on thyroid FNA cytology edited by Drs. Edmund

Cibas and Syed Ali will certainly help its application in daily

practice.

Suspicious for MalignancyThe term suspicious for malignancy should be used when the

cytological findings are suggestive but insufficient, for either

qualitative or quantitative reasons, for a definitive diagnosis

of malignancy. The subtype of the suspected

malignancy should be specified whenever possible. The cases

fall into the following subcategories: (1) suspicious for PTC

(a majority of those, 50–75%, turn out to be follicular

variant of PTC), (2) suspicious for medullary carcinoma,

(3) suspicious for other primary or secondary malignancy,

or (4) suspicious for neoplasm because of total necrosis of

lesional cells.

Figure 4. Thyroid fine-needle aspiration of papillary thyroid carcinoma. A, Subtle syncytial arrangement of thefollicular cells exhibiting numerous nuclear grooves (“coffee-bean” appearance), with fine, powdery chromatin and micronucleoli. (Papanicolaou’s stain, original magnification 400x) B, Characteristic nuclear features of papillary thyroid carcinoma with the oval nuclei, fine chromatin, nuclear grooves, micronucleoli,and intranuclear inclusions. (Papanicolaou’s stain, original magnification 600x).



A

B

MalignantThe category malignant should be used whenever the

cytological features are diagnostic of malignancy; the type

of malignancy should be specified. Cases therefore fall into

the following subcategories: (1) PTC (Figure 4),

(2) medullary carcinoma, (3) anaplastic carcinoma, or

(4) metastatic carcinoma or other malignancy.

Utilization of Ancillary Studies in Thyroid FNAAncillary studies can be performed on thyroid FNA

specimens, most commonly immunocytochemistry (usually

on cell block material; less often on smears, cytospins, or

liquid-based preparations). The most frequent applications

relate to the diagnoses of medullary thyroid carcinoma and

anaplastic carcinoma and, rarely, suspected metastasis to the

thyroid.

A suspected diagnosis of medullary thyroid carcinoma can

be confirmed by positive staining of the cells for calcitonin,

carcinoembryonic antigen (CEA), synaptophysin, CD56,

and chromogranin, with a negative thyroglobulin stain.

Findings can be correlated with serum calcitonin. The

negative staining for thyroglobulin distinguishes medullary

carcinoma from neoplasms derived from follicular

epithelium. For example, Hürthle cell neoplasms share

several cytological features (e.g., eccentric nuclei,

binucleation, and multinucleation) with medullary

carcinomas but, in contrast to the latter, Hürthle cell

neoplasms should be positive for thyroglobulin and negative

for calcitonin, chromogranin, and CEA. Of note, thyroid

transcription factor 1 (TTF-1) is not helpful in this

differential diagnosis because both medullary carcinoma

and follicular-derived neoplasms express this marker.

Immunocytochemistry can also be attempted to

differentiate anaplastic thyroid carcinoma from metastatic

carcinoma; however, it is often not useful because most

anaplastic thyroid carcinomas lose specific thyroid markers.

However, if focal expression of thyroglobulin and/or TTF-1

is seen in the context of an anaplastic malignancy, it would

support a diagnosis of anaplastic thyroid carcinoma.

Distinguishing parathyroid from thyroid follicular-pattern

lesions can be very difficult on purely cytological features,

and immunocytochemistry for TTF-1, parathyroid

hormone (PTH), and chromogranin may be useful in this

context; parathyroid lesions should be positive for

chromogranin and PTH but negative for TTF-1.

Flow cytometry may be used in thyroid FNA when

lymphoma is suspected. However, because clonal B-cell

lymphoid populations may be detected in the context of

Hashimoto’s thyroiditis without concomitant lymphoma,

caution must be exercised when interpreting flow cytometry

results. The indication for flow cytometric analysis should

therefore be based on cytomorphological or clinical features

that raise the suspicion of lymphoma; it should not be used

routinely when lymphoid material is obtained in thyroid

FNAs. Likewise, immunophenotyping results from thyroid

FNA samples should be interpreted with caution since

Hashimoto’s thyroiditis may yield kappa/lambda light chain

ratios that are skewed beyond the normal values associated

with reactive lymphoid lesions.

The use of ancillary studies to reclassify an indeterminate or

suspicious FNA into a benign or malignant category or to

refine the risk of malignancy within this category is

controversial. Although touted as potential markers for

reclassifying indeterminate or suspicious FNAs,

immunocytochemical markers (e.g., galectin-3, cytokeratin

19, and HBME-1) and the identification of chromosomal

translocations (RET/PTC, PAX8/PPARG) or of genetic

mutations (BRAF, RAS) are not recommended at this time

for widespread clinical use due to insufficient evidence.

Post-FNA Testing and Treatment OptionsFollow-Up of Nondiagnostic FNA ResultsThere is no universally accepted approach for the follow-up

of nondiagnostic FNA results. If the lesion is cystic

(i.e., consisting of blood and histiocytes without follicular

epithelium), it requires correlation with ultrasonographic

findings. If the ultrasonographic features indicate a low risk

of malignancy, the best approach is nonsurgical follow-up

with repeat FNAs at 6- to 18-month intervals. If the

ultrasonographic features are suspicious, a repeat FNA with

US-guidance (with on-site assessment if possible) is

recommended. If the repeat FNA is still nondiagnostic, close

clinical and ultrasonographic follow-up is appropriate.

If solid, a repeat FNA with US guidance (with on-site

assessment if possible) should be done. If the repeat FNA is

still nondiagnostic, surgery should be considered as the risk

AUGER


of malignancy is approximately 9%. However, close clinical

and ultrasonographic follow-up is a reasonable alternative

to surgery, particularly if the patient is reliable. When growth

of the nodule is detected during US surveillance, a repeat

FNA should preferably be performed; alternatively, the

nodule can be excised. In general, the interval between FNAs

should not be less than 3 months to avoid the pitfalls of

reparative changes.

Follow-Up of Benign FNA ResultsBecause the false-negative rate of benign FNA results is low

but not insignificant, careful clinical follow-up is

recommended. If the nodule is easily palpable, clinical

follow-up by physical examination at 6–18 months is

suggested; if it is not easily palpable, then follow-up should

include an US examination at 6–18 months.

The same approach is recommended regardless of the

number of nodules as the risk of malignancy is the same

in both situations. If suspicious features are seen

on ultrasonography, more frequent clinical and

ultrasonographic follow-ups are recommended. Because the

false-negative rate may be higher in palpation-directed FNA

than in US-guided FNA, closer follow-up is required when

FNAs are performed with palpation. Of note, thyroxine

(T4)- suppression therapy is no longer recommended under

these circumstances.

If significant growth of the nodule(s) is detected (a 20%

increase in diameter or a minimum 2 mm increase in two

dimensions), either by palpation or ultrasonography, or if a

change of ultrasonographic features occurs on follow-up, a

repeat FNA or surgical excision can be considered.

The total duration of the follow-up for benign FNA results

should be at least 3–5 years. Repeat FNA may be done under

ultrasonography, with immediate assessment of adequacy,

if possible. Alcohol ablation may be considered in select

patients who have predominantly cystic and cytologically

benign nodules.

Follow-Up of Atypia of Undetermined SignificanceBecause of the variation in criteria to date, the reported

prevalence rates of malignancy for this category have been

variable. Ninety to 95% of AUS cases represent adenomas

or dominant nodules in goitres, while approximately 5–15%

turn out to malignant. In general, the committee concluded

that a conservative approach should be adopted for atypical

thyroid FNAs. The majority of these lesions should be

re-aspirated at 3–6 months in an attempt to define them

more clearly. If the repeat FNA remains atypical, surgical

consultation should be contemplated. Also, an expert

cytopathology consultation may be considered for an initial

FNA diagnosis of AUS.

Follow-Up of an FNA with the Diagnosis “Neoplasm”The follow-up of an FNA with a diagnosis of neoplasm is

surgical exploration, usually a lobectomy. Frozen section is

not recommended for assessment of capsular invasion. If

the surgical excision shows a follicular carcinoma or the

follicular variant of PTC, a complete thyroidectomy is

usually performed; however, a lobectomy may be sufficient

for small, minimally invasive tumours.

Follow-Up of an FNA with the Diagnosis “Suspicious forMalignancy”Because 50–75% of the FNA cases diagnosed as suspicious

for malignancy turn out to be PTC, the appropriate action

is surgical consultation.

Follow-Up of an FNA with the Diagnosis “Malignant”The follow-up of an FNA diagnosed as malignant is surgical,

unless clinically contraindicated, for example, in metastatic

cancer.

ConclusionThe NCI Thyroid FNA State of the Science Conference was

a very successful interdisciplinary educational forum on the

evaluation, interpretation, and reporting of thyroid FNAs.

The standardized reporting terminology, if adopted, should

ultimately translate into improved patient diagnosis and

care.

References1. Anderson GH, Thompson DW, Kulcsar DD. Survey of cytological

facilities in Canada. CMAJ 1969;101:279–85.2. American Thyroid Association Guidelines Task Force.

Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:1–33.

3. Wang HH. Reporting thyroid FNA aspiration: literature review and a proposal. Diagn Cytopathol 2006;34:67–76.



4. Papanicolaou Society of Cytopathology Task Force on Standardsof Practice. Guidelines of the Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration specimens from thyroid nodules. Mod Pathol 1996;9:710–5.

5. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologimedical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2006;12:63–102.

6. Abati A. The National Cancer Institute Thyroid FNA State of theScience Conference: “Wrapped Up.” Diagn Cytopathol 2008;36:388–9.

7. Cibas ES, Alexander EK, Benson CB, et al. Indications for thyroidFNA and pre-FNA requirements: a synopsis of the National Cancer Institute Thyroid FNA State of the Science Conference. Diagn Cytopathol 2008;36:390–9.

8. Ljung BME, Langer J, Mazzaferri EL, et al. Training, credentialingand re-credentialing for the performance of a thyroid FNA: a synopsis of the National Cancer Institute Thyroid FNA State of the Science Conference. Diagn Cytopathol 2008;36:400–6.

9. Pitman MB, Abele J, Ali SZ, et al. Techniques for thyroid FNA: a synopsis of the National Cancer Institute Thyroid FNA State of the Science Conference. Diagn Cytopathol 2008;36:407–24.

10. Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology andmorphologic criteria for cytologic diagnosis of thyroid lesions: asynopsis of the National Cancer Institute Thyroid FNA State of the Science Conference. Diagn Cytopathol 2008;36:425–37.

11. Filie AC, Asa SL, Geisinger KR, et al. Utilization of ancillary studiesin thyroid fine needl e aspirates: a synopsis of the National CancerInstitute Thyroid FNA State of the Science Conference. Diagn Cytopathol 2008;36:438–41.

12. Layfield LJ, Abrams J, Cochand-Priollet B, et al. Post-thyroid FNAtesting and treatment options: a synopsis of the National Cancer Institute Thyroid FNA State of the Science Conference. Diagn Cytopathol 2008;36:442–8.

13. Crothers BA, Henry MJ, Auger M. NCI Thyroid Fine-Needle Aspiration State of the Science Conference: a dialogue on thyroiddisease reporting and management. CAP Today 2008;22:48–58.

14. Cibas ES. The Bethesda System for thyroid atlas project. ASC Bulletin 2009;XLVI(3):47–9.

15. Baloch WB, Cibas ES, Clark DP, et al. The National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference: a summation. Cytojournal 2008;5:6

16. Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA Cancer J Clin 2009;59:99–110.

17. Are C, Hsu JF, Schoder H, et al. FDG-PET detected thyroid incidentalomas: need for further investigation? Ann Surg Oncol 2007;14:239–47.

18. Chu QD, Conner MM, Lilien DL, et al. Positron emission tomography (PET) positive thyroid incidentaloma: the risk of malignancy observed in a tertiary referral center. Am Surg 2006;72:272–5.

19. Kresnik E, Gallowitsch HJ, Mikosch P, et al. Technetium-99M-MIBI scintigraphy of thyroid nodules in endemic goiter area. J Nucl Med 1997;38:62–5.

20. Raab SS, Vrbin CM, Grzybicki DM, et al. Errors in thyroid glandfine-needle aspiration. Am J Clin Pathol 2006;125:873–82.

AUGER


Contact Information

For Advertising Inquiries:John BirkbyADVERTISING SALES REPRESENTATIVE

[email protected]

For Classified Advertisingin Canadian Journal ofPathology Advertising:Brenda RobinsonSALES AND CIRCULATION COORDINATOR

[email protected]

Send ad materials to:115 King Street West,Suite 220,Dundas, ON L9H 1V1(905) 628-4309 | 877.245.4080866-849-1266 FAX

[email protected]

Classified Ads SpecificationsPlease fax this form along with a printed proof of your ad to 866-849-1266

in order to have your order processed.

AAdd SSiizzeess//RRaatteess:: Prices subject to change without notice.All classified ads are PPRREEPPAAYYMMEENNTT RREEQQUUIIRREEDD..black and white Canadian advertisers add 5% GST to total order.

10% discount for multiple orders.

PPlleeaassee rruunn mmyy TTeexxtt OOnnllyy CCllaassssiiffiieedd AAdd RRaattee(text only, no images, black and white only)Minimum charge for 1 – 50 words $100.00 $2.00 for each additional word over 50. ______

PPlleeaassee rruunn mmyy DDiissppllaayy CCllaassssiiffiieedd AAdd RRaatteess[ad may contain picture(s )or logo(s)]1/4 Vertical page (3.5” wide x 4.25” high) $475.001/2 Vertical page (3.375” wide x 9.5” high) $725.001/2 Horizontal page (6.875” wide x 4.625” high) $725.00Full page (8.125” wide x 10.75” high”) $1200.00

Ads must be typed and submitted in an electronic format either by mail or email to the address below. No ads will be published unless full payment andfaxed, printed proof is included with order.

Ad to appear in: Issue 1 (Feb) Issue 2 (May) Issue 3 (Aug) Issue 4 (Oct)

CCOONNTTAACCTT IINNFFOO::

NAME: TITLE:

ORGANIZATION: AGENCY NAME:

ADDRESS:

CITY/TOWN: POSTAL CODE:

PHONE: FAX:

EMAIL:

Advertising Terms Andrew John Publishing Inc. (AJPI) is not responsible for any errors in elec-tronic files supplied by the client. Similarly, AJPI accepts no responsibility forpoor reproductions as a result of client-supplied materials. The advertiser andthe advertising agency assume full liability for all advertising submitted, print-ed, or published. Ads not received on deadline may not be run. If not pub-lished, advertisers will be charged a 50% space-holding fee.

www.andrewjohnpublishing.com

2010 Advertising Rates

Canadian Journal of

Pathology Canadian Journal of

Pathology

Canadian Journal of

Pathology

An Official Publication of the Canadian Association of Pathologists (CAP)


$100.00 $

$1200.00

A

Issue 2 (M Issue 3 (A Issue 4 (O

The Canadian Association of Pathologists is a voluntary professional organization of laboratory physicians and scientists. The CAP’s mission is to provide national leadership in Pathology and Laboratory Medicine through the promotion of excellence in practice, education and research, and through the fostering of integrity and high standards of ethical behaviour. The CAP aims to provide continuing professional development to all subgroups within its membership. The CAP will also advocate for high quality and standards for patient care, promote collegiality and advocate for the professional interests of laboratory physicians and scientists.

CANADIAN ASSOCIATION OF PATHOLOGISTSCONTINUING PROFESSIONAL DEVELOPMENT CO-ORDINATOR

(Independent Consultant Position)

The Canadian Association of Pathologists (CAP) has established a search committee to seek candidates for the Contract Position of Continuing Professional Development (CPD) Coordinator. As the consultant, you have a background in adult education BA, MA or PhD. You are a highly respected professional and leader with a compel-ling vision for continuing professional development. You have knowledge of adult-education principles and current practice, good working knowledge of medical English, good interpersonal skills and are computer savvy.

Job SummaryThe activities outlined below are indicative of the services required by the CAP for this position.

Working closely with the Continuing Professional Development (CPD) Committee and the National Standards Immunohistochemistry Committee, the CPD Coordinator will develop and implement a standardized CPD program for Canadian Pathologists. You understand the mission of the CAP in providing quality educational materials and will be thoroughly familiar with the Royal College of Physicians and Surgeons of Canada Maintenance of Certification Program, and continuing medical education (CME) requirements. You will collaborate with the Association Manager in the CAP office, supporting and communicating with membership via telephone, e-mail and website updates. Your ability to liaise with other organizations (i.e., provincial, other national and international sections) will facilitate the collection of pathology cases.

The Consultant is engaged as an independent Consultant providing services to the Canadian Association of Pathologists (CAP), and is not engaged as an employee or agent of the Canadian Association of Pathologists.

Qualifications • Proficient in a variety of computer applications including use of data processing and bookkeeping• Excellent oral, written, analytical and technical skills • Experience in formulating educational objectives goals and programs• Ability to work closely with professionals and internal and external partners• Bookkeeping and management of funds flowing through this initiative• Ability to manage data in a reliable manner with easy retrieval• Ability to multitask and to function independently as, and when, necessary • Strong organizational and planning skills• Background in journalism would be an asset

Each project will have a detailed comprehensive statement of the objectives and needs required, including timelines and deliverables. A work plan will be constructed according to the project requirements.

Reports of work in progress will be necessary for each project summarizing in detail the next steps, time allocated to each, desired results and measurements of success in achieving the goals and objectives of each project.

Commencement and Completion of ProjectThe work will start November 2009 as determined after joint discussions with the applicant and the CAP. You must be available to work during business hours.

Manner of PaymentPayment will be on a monthly basis based on an hourly rate to be determined.

A review of documents and materials will be made available to the consultant providing information about the CAP.

To apply for this position, please forward your résumé, covering letter and salary expectations, by January 29, 2010, via electronic address: [email protected]

Dr. Joan Sweet, Chair of the Search Committee, Canadian Association of Pathologists - 774 Echo Drive, Ottawa, ON K1S 5N8

The CAP is an equal opportunity employer. In the first instance, preference will be give to Canadian citizens and those with permanent status in Canada.

We thank all applicants for their interest; however, only those under consideration will be contacted.


DISPLAY CLASSIFIEDS

Forensic Pathologist Hamilton Regional Laboratory Medicine Program

and McMaster University

Hamilton, Ontario

Applications are invited for a full-time Forensic Pathologist position with the Hamilton Regional Laboratory Medicine Program (HRLMP). The Forensic Pathology Unit is a sub-specialty of the Anatomic Pathology section of the HRLMP and is geographically located at the General Hospital site of Hamilton Health Sciences. The Unit has two full-time Forensic Pathologists, with faculty appointments in the Department of Pathology and Molecular Medicine, McMaster University. As part of our Academic Health Sciences Centre, support is available from other branches of laboratory medicine including in-house consultation with neuropa-thology and cardiovascular pathology. Pediatric and other sub-specialty pathologists are readily available for consultation. The area served has a population of over 1.5 million, and extends from Halton in the east, Simcoe in the west, Guelph in the north and Niagara Falls in the south. The combination of heavy industry, urban, farming, recreational and seasonal communities presents a unique experience of cases. Annually, 650 - 700 complete autopsies are performed with a large cross-section of experience in suicides, natural deaths, accidents (especially industrial), motor vehicle traumas, pediatric deaths, complex in-hospital and medical legal investigations, nursing home deaths, psychiatric institutional deaths, correctional and other in-custody deaths, and 30 - 40 homicides. Experience in giving testimony in provincial courts is required. The successful candidate is expected to teach undergraduate and medical students, residents in pathology and clinical programs, as well as representatives of law enforcement agencies and the judiciary. In anticipation of the Royal College of Physicians & Surgeons of Canada (RCPSC) approval of an accredited forensic pathology fellowship program, full participation in teaching such trainees is mandatory. Research is highly encouraged and expected. Interested candidates should have RCPSC Specialty certification or equivalent in either Anatomic or General Pathology, with additional training in Forensic Pathology, and be eligible for medical licensure in Ontario. The individual will be required to pass the RCPSC subspecialty examination in forensic pathology within two years of appointment.Interested candidates are invited to submit a cover letter, curricu-lum vitae and the names and addresses of three referees by Decem-ber 31, 2009 to:Dr. Vina AlexopoulouDirector, Anatomical Pathology, and Deputy Chief,Hamilton Regional Laboratory Medicine ProgramProfessor of Pathology and Molecular MedicineMcMaster University, HSC 2N191200 Main Street WestHamilton ON L8N 3Z5Phone: 905 521-2100, Ext. 76295 Fax: 905 577-8468Email: [email protected] interested and qualified candidates are encouraged to apply; however, Canadians and permanent residents will be given priority. Hamilton Regional Laboratory Medicine Program and McMaster University are committed to employment equity and welcome applications from all qualified persons. The positions will remain open until filled.

Academic Pediatric Pathologist Hamilton Regional Laboratory Medicine Program

and McMaster University

Hamilton, Ontario

A position in Pediatric/Perinatal Anatomical Pathology is available in the Hamilton Regional Laboratory Medicine Program (HRLMP) and the Department of Pathology and Molecular Medicine at McMaster University. This full-time joint appointment in a large academic centre presents an excellent opportunity for an experienced academic pediatric pathologist or a recent graduate currently completing a pediatric pathology fellowship. The Hamilton Children’s Hospital is the second largest children’s hospital in Ontario. The successful candidate will share service responsibilities with two other full-time pediatric pathologists as part of a larger regional anatomic pathology group with expertise in all pathology subspecialties, including neuropathology and forensic pathology. The Department of Pathology and Molecular Medicine is active in both undergraduate and postgraduate trainee teaching and members are expected to participate in research activities. The successful candidate will be presented for a faculty appointment, and academic rank will be determined by the qualifications of the applicant. The position is available as of January 1, 2010.Applicants must be certified in Anatomical Pathology by the Royal College of Physicians and Surgeons of Canada or equivalent and must be eligible for registration with the College of Physicians and Surgeons of Ontario.The City of Hamilton has a population of 500,000 and is home to six friendly and family-oriented communities, nestled against the picturesque Niagara escarpment on the western edge of Lake Ontario. A relaxed, culturally diverse atmosphere with excellent schools makes Hamilton an attractive place for families. Outdoor enthusiasts enjoy the excellent local hiking, climbing and mountain biking. The pleasures of wine country can be enjoyed in nearby Niagara, and more cosmopolitan opportunities – be it theater, fine dining or professional sports – abound in Toronto, both only 45 minutes away. Interested candidates are invited to submit a cover letter, curricu-lum vitae and the names and addresses of three referees by Decem-ber 31, 2009 to:Dr. Vina AlexopoulouDirector, Anatomical Pathology, and Deputy Chief, Hamilton Regional Laboratory Medicine ProgramProfessor of Pathology and Molecular MedicineMcMaster University, HSC 2N191200 Main Street WestHamilton ON L8N 3Z5Phone: 905 521-2100, Ext. 76295 Fax: 905 577-8468Email: [email protected] interested and qualified candidates are encouraged to apply; however, Canadians and permanent residents will be given priority. Hamilton Regional Laboratory Medicine Program and McMaster University are committed to employment equity and welcome applications from all qualified persons. The position will remain open until filled

DISPLAY CLASSIFIEDS


ANATOMIC PATHOLOGY POSITION The Department of Laboratory Medicine at St. Michael’s Hospital invites applications for a full time faculty position as an Anatomic Pathologist in the Division of Pathology. The successful candidate will receive an academic appointment in the Department of Laboratory Medicine and Pathobiology, University of Toronto, with the appropriate academic rank.

Applicants must have a M.D. or M.D./Ph.D. degree and be certified in Anatomic Pathology by the Royal College of Physicians and Surgeons of Canada, or equivalent. Requirements include formal training and experience in general surgical pathology, excellent diagnostic skills, and strong academic credentials. The position involves diagnostic service, teaching, and development of a collaborative research program in clinical, applied or basic research.

The Division of Pathology has 16 pathologists and is affiliated with 4 other divisions in the Department of Laboratory Medicine. A molecular biology laboratory is associated with anatomic pathology, as well as automated immunohistochemistry and electron microscopy services.

The University of Toronto is strongly committed to diversity within its community and especially welcomes applications from visible minority group members, women, Aboriginal persons, persons with disabilities, members of sexual minority groups and others who may contribute to the further diversification of ideas.

A letter of interest, and a list of references, should be sent with a C.V. before December 31, 2009, or until position is filled, to:

Dr. Serge Jothy, Chief, Department of Laboratory MedicineSt. Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8

Tel: (416) 864 5972 Fax: (416) 864-5648E-Mail: [email protected]

PART-TIME POSITION – PETERBOROUGH REGIONAL HEALTH CENTRE

The Department of Laboratory Medicine at the Peterborough Regional Health Centre is seeking a pathologist trained in general pathology to fill a part-time position (0.4 FTE), vacant due to a recent retirement. The successful applicant will share responsibility with another general pathologist who also works part-time, and will be responsible for hematopathology sign-out and for supervision of the clinical pathology lab (core, microbiology, and transfusion medicine), as well as participation in the surgical pathology sign-out rotation.

Interested individuals may send a letter of application, including curriculum vitae, in confidence to:Dr. Virginia M. WalleyMedical Director and ChiefLaboratory MedicinePeterborough Regional Health Centre1 Hospital Dr.Peterborough, ONK9J 7C6or by email to: [email protected]

DISPLAY CLASSIFIEDS

To inquire about rates or to submit material to advertise in Canadian Journal of Pathology, please contact Brenda Robinson:

T: 905.628.4309 | E: [email protected]

Subject to availability. Book early! Canadian Journal of P athology 45Winter 2009

n c p

*Strategic Training Initiative in Health Research

MOLECULAR ONCOLOGIC PATHOLOGY FELLOWSHIP PROGRAM in CANADA

Toronto, Kingston, Vancouver, Victoria, Calgary

Openings for 2010 - 11

“TFF STIHR* in Molecular Pathology of Cancer at CIHR” is funded jointly by the Terry Fox Foundation (TTF) and the Canadian Institutes of Health Research (CIHR). This is a specialized research training program for “Clinician-Scientists in Molecular Oncologic Pathology”, available at any of the four training centres: Toronto: Princess Margaret Hospital/Ontario Cancer Institute Kingston: Queen’s University Vancouver/Victoria: BC Cancer Agency, Vancouver and Vancouver Island Centres Calgary: Alberta Cancer Research Institute and Tom Baker’s Cancer Centre

Accepted fellows are funded by the program for 2 years to receive research training in the pathobiology and molecular pathology of human cancer. Trainees will be exposed to a comprehensive range of leading edge laboratory techniques and their applications to molecular pathology research. In addition to formal and self-directed learning, each fellow undertakes an in-depth research project that should lead to publication in high impact journals. Fellows may elect to combine or continue this training program in post-graduate studies that lead to a M.Sc. or Ph.D. degree. This Training Program is designed for MD/MBChB pathologists who will have completed their residency or clinical fellowship and wish to develop additional research expertise for an academic career in molecular pathology. For further information and application details please contact: Dr. Ming-Sound Tsao Tel. (416) 340-4737; e-mail: [email protected] or Margaret Juszczak Tel. (416) 340-4800 ext. 5938; E-mail: [email protected] Website: http://molecularpathology.ca

50072 12MAY09

The new vision of special stains automation and connectivityDakoLink Special Stains Solution

The next advance in workflow optimization has arrived with the DakoLink Special Stains Solution featuring the next generation ArtisanLink and Dako ready-to-use reagents. This system combines true automation with network connectivity and provides the best of both worlds with Dako IVD-validated reagents and customizable staining protocols to deliver high-quality and reproducible results every time.

High Quality. Enhanced Productivity. Fast Turnaround Time. ArtisanLinkwww.dako.com

Princess Margaret Hospital/Ontario Cancer Institute

K Queen’s University V

Trainees will be exposed to a

c In addition to formal and self-directed learning, each fellow

u Fellows may elect to combine or continue this training program in post-graduate

s

M

h

Do you require temporarypathology assistance?We can help.When you require back upservices due to pathologistor technologist shortages,we can provide you withoutsourced pathology andhistology services.

We assist hospitals and privateclinic facilities across Canada.

We can provide customizedservices such as:• Technical only (grossing,processing, microtomyand staining)

• Full service (technical,professional interpretationand report)

• Professional services only(professional interpretationand report)

For more information:

Call: 647.232.5302Email: hospitalservices@

gamma dynacare.com

Visit us at www.gamma dynacare.com.

cpanadaian jtourhnal ofolog y - canadian journal of...

Documents